WO2013077533A1 - Chewable sildenafil citrate tablets in which bitterness is masked, and production method therefor - Google Patents

Chewable sildenafil citrate tablets in which bitterness is masked, and production method therefor Download PDF

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Publication number
WO2013077533A1
WO2013077533A1 PCT/KR2012/006856 KR2012006856W WO2013077533A1 WO 2013077533 A1 WO2013077533 A1 WO 2013077533A1 KR 2012006856 W KR2012006856 W KR 2012006856W WO 2013077533 A1 WO2013077533 A1 WO 2013077533A1
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Prior art keywords
sildenafil citrate
chewable
weight
comparative example
tablet
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PCT/KR2012/006856
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French (fr)
Korean (ko)
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최연웅
민병구
조상민
기도형
이병훈
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한국유나이티드제약 주식회사
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Publication of WO2013077533A1 publication Critical patent/WO2013077533A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a method for preparing chewable tablets of sildenafil citrate which is easy to take as a therapeutic agent for erectile dysfunction and is masked by bitter taste.
  • sildenafil is 1 [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4- Sildenafil and its pharmaceutically acceptable salts with ethoxyphenyl] sulfonyl] -4-methylpiperazine are described in European Patent Publication No. 0463756.
  • Sildenafil acts as a selective inhibitor of cyclic guanosine 3'5'-monophosphate phosphodiesterase type 5 (cGMP PDE5) and can be used for the treatment of impotence in Korean Patent No. 10-0262926. Yes is described.
  • cGMP PDE5 cyclic guanosine 3'5'-monophosphate phosphodiesterase type 5
  • it is commercially available as an oral tablet formulated using a form of citrate salt with improved solubility and absorption for oral administration of the substance (Viagra, Pfizer).
  • the citrate salt of sildenafil is easy to administer with water in the form of a film-coated tablet, but it is difficult to formulate it into a liquid, gum, oral disintegrating tablet, and chewed tablet which are convenient to take due to the bitter taste in the oral cavity.
  • Korean Patent Publication No. 10-1999-0017127 discloses a porous tablet using a free base of sildenafil.
  • the formulations do not feel bitter in the oral cavity due to the low solubility of sildenafil free base, but have a limitation of low bioavailability due to the low solubility and absorption of sildenafil free base.
  • Korean Patent No. 10-0435514 describes a method for improving the bitter taste of sildenafil citrate salt using sildenafil lactate.
  • Korean Patent No. 10-0344198 describes a method of formulating by masking the bitter taste of sildenafil citrate salt using a sweetening agent, a copulating agent, a flavoring agent, a masking agent, and the like. However, this method does not completely mask the bitter taste of sildenafil citrate salt.
  • the present invention has the object of developing a formulation that improves compliance with medication by developing a chewable tablet that is completely unmasked when taken by completely masking the bitter taste of sildenafil citrate salt and is easy to administer.
  • a sildenafil citrate chewable tablet in which a bitter taste is masked using an additional cyclic group after the mask is bitter using an ion exchange resin having a carboxyl group.
  • the additive is characterized in that it comprises 10 to 70% by weight of the total weight of the chewable tablet.
  • polyvinylpyrrolidone polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, xanthan gum, sodium alginate and water dispersibility
  • binders selected from the group consisting of starch is characterized in that it comprises 0.5 to 20% by weight of the total weight of chewable tablets.
  • one or two or more disintegrants selected from the group consisting of crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, sodium starch glycolate and calcium carboxymethylcellulose It is characterized in that it comprises 0.5 to 30% by weight of the total weight of the chewable tablets.
  • the sildenafil citrate which is the active ingredient sildenafil citrate salt, ion exchange resin and cyclodextrin by reacting in a solvent to mask the bitter taste and then tableting immediately after mixing without going through a separate process Provides a method of manufacturing cheongjeong.
  • the chewable tablets of sildenafil citrate salt prepared according to the present invention are expected to be very useful when administered to a patient because of rapid dissolution and bitter taste in terms of masking, and ease of taking.
  • the present invention is characterized by providing a chewable tablet that is easy to take by masking the bitter taste of sildenafil citrate salt, a PDE-5 (phosphodiesterase-5) inhibitor, as an active ingredient.
  • sildenafil citrate salt having a bitter taste is adsorbed to an ion exchange resin having a carboxyl group, the drug is not released in the oral cavity and the drug is released by exchanging the drug with other ions in the digestive tract so that the bitter taste is not felt in the oral cavity. It is possible to take the drug.
  • the inclusion of the sildenafil citrate salt was performed together with the cyclodextrin. As a result, it has been found that the masking of bitterness is more complete and the dissolution rate is improved. In addition, by reducing the amount of ion exchange resin used to improve the fluidity and compressibility was also able to solve the process problems.
  • the sildenafil citrate salt used as an active ingredient in the present invention may contain 25 to 100 mg of sildenafil per tablet.
  • the ion exchange resin contains 10 to 30% by weight, preferably 13 to 20% by weight of the total formulation, and cyclodextrin contains 5 to 40% by weight, preferably 10 to 20% by weight of the total formulation. Good to do.
  • the chewable tablet of the present invention contains a saccharide, a binder, a disintegrant, a flavoring agent, a sweetening agent, a lubricant, and the like, which are commonly used in the art as a pharmaceutically acceptable carrier for preparing the formulation.
  • the sugar is an important ingredient that affects the dissolution and absorption of the active ingredient, as well as sweetness, solubility, and touch in the mouth, and should have a good taste, feel, and water solubility in the oral cavity, and the mouth size should be small enough to be free from foreign substances.
  • Sugars that can be used include lactose, mannitol, sorbitol, xylitol, erythritol, glucose, sucrose, fructose, rebulose, maltodextrin, paratinose and the like.
  • the saccharide preferably contains 10 to 70% by weight, preferably 20 to 50% by weight of the total formulation.
  • the binder is a component necessary to exhibit strength in the chewable tablet of the present invention and is used for the purpose of maintaining the shape of the product during handling and storage of the product.
  • polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, hydroxypropylmethylcellulose, gum arabic, xanthan gum, sodium alginate, water-dispersible starch and derivatives may be used.
  • the binder is preferably contained 0.5 to 20% by weight, preferably 1 to 10% by weight of the total formulation.
  • the disintegrant component is a component for quickly disintegrating the chewable tablet of the present invention is an important component in the dissolution, absorption of the active ingredient.
  • cross-linked polyvinylpyrrolidone cross-linked carboxymethyl cellulose, sodium starch glycolate, calcium carboxymethyl cellulose, and the like may be used, and preferably cross-linked carboxymethyl cellulose is used.
  • the disintegrant preferably contains 0.5 to 30% by weight, preferably 2 to 10% by weight of the total formulation.
  • the chewable tablet according to the present invention in addition to the above components in the range that does not impair the effects of the present invention, for example, lubricant components such as magnesium stearate, talc, sodium stearyl fumarate and aspartame, stevioside, sucralose Sweeteners, strawberry flavors, blueberry flavors, orange flavors such as flavoring agents, blue No. 1, yellow No. 4, red No. 2 and other colorants may be further included as a pharmaceutical additive to aid in formulating. .
  • lubricant components such as magnesium stearate, talc, sodium stearyl fumarate and aspartame, stevioside, sucralose Sweeteners, strawberry flavors, blueberry flavors, orange flavors such as flavoring agents, blue No. 1, yellow No. 4, red No. 2 and other colorants may be further included as a pharmaceutical additive to aid in formulating. .
  • a chewable tablet was prepared using the above ingredients. Manufacturing process 1
  • the chewable tablet was manufactured through the tableting step.
  • the selection of a suitable solvent for the shielding and the bonding liquid is relatively free, whereas in the preparation process 2 1, the solvent which can be used as the bonding liquid at the same time as the shielding of the main components should be selected.
  • the amount is bound to be limited.
  • the inventors prepared a chewable tablet by mixing the shielded main component, ion exchange resin, and beta-cyclodextrin with excipients without tableting. This manufacturing process 3
  • a chewable tablet was prepared by the step of tableting.
  • sildenafil citrate The chewable tablets of sildenafil citrate were prepared according to Preparation 3 using the ingredients and contents shown in Table 1 below.
  • Sildenafil citrate, polyacrylic potassium and beta-cyclodextrin are dispersed in purified water (0.5 g per tablet) using a stirrer and shielded. It is left to stand for 8 hours and then dried at 50 ° C. After drying, the mixture was formed into a No. 20 sieve and mixed with mannitol, hydroxypropyl cellulose, croscarmellose sodium, stevioside, blueberry flavored Lac, and magnesium stearate.
  • the strength at the time of tableting is 7 to 12 KP.
  • Example 1 Sildenafil Citrate 140.45 140.45 Polyacrylic potassium 100.00 140.00 Beta-cyclodextrin 70.00 70.00 Mannitol 247.55 207.55 Hydroxypropyl cellulose 10.00 10.00 Croscarmellose Sodium 48.00 48.00 Stevioside 2.00 2.00 Blueberry Flavored Coton 2.00 2.00 Magnesium stearate 14.00 14.00 Total weight 634.00 634.00
  • a chewable tablet of sildenafil citrate salt was prepared according to Preparation Process 1, using the same ingredients and contents as in Example 1 described in Table 1.
  • Sildenafil citrate, polyacrylic potassium and beta-cyclodextrin are dispersed in purified water (0.5 g per tablet) using a stirrer and shielded. It is left to stand for 8 hours and then dried at 50 ° C.
  • the mixture was formed into a No. 20 sieve, mannitol, half croscarmellose sodium, and blueberry flavored Lacs were mixed, and hydroxypropyl cellulose was dissolved in purified water (0.1 g per tablet) and added.
  • Granules were granulated to 1.5 ⁇ using a granulator, then dried at 50 ° C., sieved to No. 20, and then mixed with stevioside and magnesium stearate and compressed into tablets.
  • the strength at the time of tableting is 7 to 12 KP.
  • a chewable tablet of sildenafil citrate salt was prepared in Preparation Process 2, using the same ingredients and contents as in Example 1, described in Table 1.
  • Sildenafil citrate, polyacrylic potassium and beta-cyclodextrin are dispersed in 80% ethanol (w / w, 0.35 g per tablet) using a stirrer, shielded and hydroxypropylcellulose is added to form a binding solution. After 8 hours, the binding solution is added to the mixture of mannitol, half croscarmellose sodium and blueberry flavored Lac.
  • Granules were granulated to 1.5 ⁇ using a granulator, then dried at 50 ° C., sieved to No. 20, and then mixed with stevioside and magnesium stearate and compressed into tablets. The strength at the time of tableting is 7 to 12 KP.
  • the dissolution test of sildenafil citrate salt was carried out as follows.
  • Dissolution method Method 1 of dissolution test of Korea Pharmacopoeia (Basket method)
  • UV wavelength 290 nm
  • Example 1 and Example 2 prepared by chewing tablet using polyacrylic potassium and beta-cyclodextrin was completely masked bitter taste, the yield was high as 97%, The dissolution rate was also higher than that of the comparative example.
  • the chewable tablets of sildenafil citrate salt prepared according to the present invention are expected to be very useful when administered to a patient because of the quickness of dissolution and bitter taste in terms of masking and ease of taking.

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Abstract

The present invention relates to a method for producing chewable tablets of sildenafil citrate, a therapeutic agent for erectile dysfunction, in which the bitterness of the sildenafil citrate is masked and which are easy to take, and the invention provides chewable sildenafil citrate tablets in which the bitterness is masked by the use of an ion-exchange resin having a carboxyl group. The chewable sildenafil citrate salt tablets produced in accordance with the present invention are outstanding in terms of rapidity of elution and concealment of bitterness, and are easy to take and can therefore be expected to be very useful when administered to patients.

Description

쓴맛이 차폐된 실데나필 시트레이트의 저작정 및 이의 제조방법Chewing Tablet of Bitter Taste Sildenafil Citrate and Manufacturing Method Thereof
본 발명은 발기부전 치료제로서 복용이 간편하고 쓴맛이 차폐된 실데나필 시트레이트의 저작정을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing chewable tablets of sildenafil citrate which is easy to take as a therapeutic agent for erectile dysfunction and is masked by bitter taste.
실데나필의 화학명은 1[[3-(6,7-디하이드로-1-메틸-7-옥소-3-프로필-1H-피라졸로[4,3-d]피리미딘-5-일)-4-에톡시페닐]설포닐]-4-메틸피페라진으로 실데나필 및 그의 약학적으로 허용가능한 염이 유럽 특허 공개공보 제 0463756호에 기재되어 있다. The chemical name of sildenafil is 1 [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4- Sildenafil and its pharmaceutically acceptable salts with ethoxyphenyl] sulfonyl] -4-methylpiperazine are described in European Patent Publication No. 0463756.
실데나필은 사이클릭 구아노신 3’5’-모노포스페이트 포스포디에스터라제 제 5형(cGMP PDE5)의 선택적 억제제로 작용하며 대한민국 특허 제 10-0262926호에서 임포텐스(발기부전)의 치료용으로 사용할 수 있음이 기재되어 있다. 또한 상기물질의 경구투여를 위해 용해도와 흡수성이 향상된 시트레이트염의 형태를 이용하여 제제화한 경구용 정제로 시판되고 있다(비아그라, 화이자사). Sildenafil acts as a selective inhibitor of cyclic guanosine 3'5'-monophosphate phosphodiesterase type 5 (cGMP PDE5) and can be used for the treatment of impotence in Korean Patent No. 10-0262926. Yes is described. In addition, it is commercially available as an oral tablet formulated using a form of citrate salt with improved solubility and absorption for oral administration of the substance (Viagra, Pfizer).
그러나 실데나필의 시트레이트염은 필름코팅정의 형태로 물과 함께 투여시에는 용이하나 구강 내에서의 쓴맛으로 인해 복용이 편리한 액제, 껌, 경구붕해정, 저작정 등으로 제제화하기는 어렵다. However, the citrate salt of sildenafil is easy to administer with water in the form of a film-coated tablet, but it is difficult to formulate it into a liquid, gum, oral disintegrating tablet, and chewed tablet which are convenient to take due to the bitter taste in the oral cavity.
이를 해결하기 위해 대한민국 특허공개 제 10-1999-0017127호에서는 실데나필의 유리 염기를 사용한 다공성 정제를 기재하였다. 상기 제제는 실데나필 유리 염기의 낮은 용해도로 인해 구강 내에서 쓴맛을 느끼지 못하게 하지만 실데나필 유리 염기가 갖는 낮은 용해도와 흡수성에 의해 생체이용율이 낮다는 한계를 가진다. 또한 대한민국 특허 제 10-0435514호에서는 실데나필 젖산염을 사용하여 실데나필 시트레이트염의 쓴맛을 개선시키는 방법을 기재하였다. In order to solve this problem, Korean Patent Publication No. 10-1999-0017127 discloses a porous tablet using a free base of sildenafil. The formulations do not feel bitter in the oral cavity due to the low solubility of sildenafil free base, but have a limitation of low bioavailability due to the low solubility and absorption of sildenafil free base. In addition, Korean Patent No. 10-0435514 describes a method for improving the bitter taste of sildenafil citrate salt using sildenafil lactate.
또한 대한민국 특허 제 10-0344198호에서는 감미제 및 교미제와 착향제, 마스킹화제 등을 사용하여 실데나필 시트레이트염의 쓴맛을 차폐하여 제제화하는 방법에 대해 기재하였다. 하지만 상기 방법으로 실데나필 시트레이트염의 쓴맛을 완전히 차폐할 수 없다. In addition, Korean Patent No. 10-0344198 describes a method of formulating by masking the bitter taste of sildenafil citrate salt using a sweetening agent, a copulating agent, a flavoring agent, a masking agent, and the like. However, this method does not completely mask the bitter taste of sildenafil citrate salt.
또한 국제출원특허 WO 09/074995에서는 이온교환수지와 감미제를 이용해 실데나필 시트레이트염의 쓴맛을 차폐하는 방법을 기재하였다. 하지만 상기 방법은 여러 공정을 거쳐야 하여 경제성이 떨어지고 대량 생산이 불가능하며 쓴맛의 차폐가 완전하지 못하고 용출률이 떨어지는 단점을 가진다. International application WO 09/074995 also describes a method for masking the bitter taste of sildenafil citrate salt using an ion exchange resin and a sweetener. However, the above method has disadvantages in that it is economical, cannot be mass-produced, the masking of bitterness is incomplete and the dissolution rate is lowered through several processes.
이에 본 발명은 실데나필 시트레이트염의 쓴맛을 완전히 차폐하여 복용시 거부감이 없고 투여가 간편한 저작정을 개발하여 복약순응도가 개선된 제제를 개발하는데 그 목적이 있다. Accordingly, the present invention has the object of developing a formulation that improves compliance with medication by developing a chewable tablet that is completely unmasked when taken by completely masking the bitter taste of sildenafil citrate salt and is easy to administer.
본 발명의 적절한 실시 형태에 따르면, 카르복실기를 가지는 이온교환수지를 사용하여 쓴맛을 차폐한 후, 싸이클로 텍스트린을 추가로 사용하여 쓴맛을 차폐한 실데나필 시트레이트 저작정을 제공한다.According to a preferred embodiment of the present invention, a sildenafil citrate chewable tablet is provided in which a bitter taste is masked using an additional cyclic group after the mask is bitter using an ion exchange resin having a carboxyl group.
본 발명의 다른 적절한 실시 형태에 따르면, 유당, 만니톨, 솔비톨, 크실리톨, 에리스리톨, 글루코즈, 수크로즈, 과당, 레불로즈, 말토덱스트린, 및 파라티노즈로 이루어진 군에서 선택된 1종 또는 2종 이상의 첨가제를 저작정 전체중량의 10 내지 70 중량% 로 포함하는 것을 특징으로 한다.According to another suitable embodiment of the present invention, one or two or more selected from the group consisting of lactose, mannitol, sorbitol, xylitol, erythritol, glucose, sucrose, fructose, rebulose, maltodextrin, and paratinose The additive is characterized in that it comprises 10 to 70% by weight of the total weight of the chewable tablet.
본 발명의 다른 적절한 실시 형태에 따르면, 폴리비닐피롤리돈, 비닐피롤리돈과 비닐아세테이트의 코폴리머, 히드록시프로필셀룰로오즈, 히드록시프로필메틸셀룰로오즈, 아라비아검, 크산탄검, 알긴산 나트륨 및 수분산성 전분으로 이루어진 군에서 선택된 1종 또는 2종 이상의 결합제를 저작정 전체중량의 0.5 내지 20 중량% 로 포함하는 것을 특징으로 한다.According to another suitable embodiment of the invention, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, xanthan gum, sodium alginate and water dispersibility One or two or more binders selected from the group consisting of starch is characterized in that it comprises 0.5 to 20% by weight of the total weight of chewable tablets.
본 발명의 다른 적절한 실시 형태에 따르면, 가교결합된 폴리비닐피롤리돈, 가교결합된 카르복시메칠셀룰로오스, 소디움 스타치 글리콜레이트 및 칼슘 카르복시메틸셀룰로오스로 이루어진 군에서 선택된 1종 또는 2종 이상의 붕해제를 저작정 전체중량의 0.5 내지 30 중량% 로 포함하는 것을 특징으로 한다.According to another suitable embodiment of the present invention, one or two or more disintegrants selected from the group consisting of crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, sodium starch glycolate and calcium carboxymethylcellulose It is characterized in that it comprises 0.5 to 30% by weight of the total weight of the chewable tablets.
본 발명의 또 다른 적절한 실시 형태에 따르면, 유효성분인 실데나필 시트레이트염, 이온교환수지 및 싸이클로덱스트린을 용매에서 반응시켜 쓴맛을 차폐한 공정 후 별도의 공정을 거치지 않고 혼합 후 바로 타정하는 실데나필 시트레이트 저작정의 제조방법을 제공한다.According to another suitable embodiment of the present invention, the sildenafil citrate which is the active ingredient sildenafil citrate salt, ion exchange resin and cyclodextrin by reacting in a solvent to mask the bitter taste and then tableting immediately after mixing without going through a separate process Provides a method of manufacturing cheongjeong.
본 발명에 따라서 제조된 실데나필 시트레이트염의 저작정은 용출의 신속함과 쓴맛이 마스킹측면에서 우수하고, 복용이 간편하므로 환자에게 투여시 매우 유용할 것으로 기대된다.The chewable tablets of sildenafil citrate salt prepared according to the present invention are expected to be very useful when administered to a patient because of rapid dissolution and bitter taste in terms of masking, and ease of taking.
본 발명은 유효성분으로 PDE-5(phosphodiesterase-5) 억제제인 실데나필 시트레이트염의 쓴맛을 차폐함으로써 복용이 간편한 저작정을 제공함을 그 특징으로 한다. The present invention is characterized by providing a chewable tablet that is easy to take by masking the bitter taste of sildenafil citrate salt, a PDE-5 (phosphodiesterase-5) inhibitor, as an active ingredient.
쓴맛을 차폐하기 위하여, 이온교환수지를 사용하여 실데나필 시트레이트염의 차폐를 시도하였다. 쓴맛을 나타내는 실데나필 시트레이트염을 카르복실기를 갖는 이온교환 수지에 흡착시키는 경우, 구강 내에서는 약물이 방출되지 않고 소화관 내에서 다른 이온과 약물의 교환에 의해 약물이 방출되기 때문에 구강 내에서 쓴맛을 느끼지 못하고 약물을 복용하는 것이 가능하다. In order to mask the bitterness, an attempt was made to shield the sildenafil citrate salt using an ion exchange resin. When the sildenafil citrate salt having a bitter taste is adsorbed to an ion exchange resin having a carboxyl group, the drug is not released in the oral cavity and the drug is released by exchanging the drug with other ions in the digestive tract so that the bitter taste is not felt in the oral cavity. It is possible to take the drug.
하지만 이온교환 수지만으로 실데나필 시트레이트염의 쓴맛을 차폐할 경우 실데나필 시트레이트염과 이온교환수지의 비가 1 : 0.7 이상의 많은 양의 이온교환 수지가 사용되어야 하고, 이 경우 이온교환수지의 유동성과 압축성이 좋지 않아 타정시 정제의 강도가 좋지 못하고 정제의 질량이 균일하지 않는 문제점이 발견되었다. 또한 용출률이 떨어지는 단점이 있었다. However, when only the ion exchange resin is used to mask the bitter taste of sildenafil citrate salt, a large amount of ion exchange resin having a ratio of sildenafil citrate salt and ion exchange resin of 1: 0.7 or more must be used, in which case the flowability and compressibility of the ion exchange resin is poor. As a result, a tablet was found to have a problem of poor tablet strength and uneven mass of tablets. In addition, the dissolution rate was lowered.
이에 본 발명은 싸이클로덱스트린을 함께 사용하여 실데나필 시트레이트염의 포접을 같이 실행하였다. 이로 인해, 쓴맛의 차폐가 더욱 완전해지고 용출률을 향상시키는 것을 발견하였다. 또한 이온교환수지의 사용량을 줄임으로써 유동성과 압축성을 개선하여 공정상의 문제점 또한 해결할 수 있었다. In the present invention, the inclusion of the sildenafil citrate salt was performed together with the cyclodextrin. As a result, it has been found that the masking of bitterness is more complete and the dissolution rate is improved. In addition, by reducing the amount of ion exchange resin used to improve the fluidity and compressibility was also able to solve the process problems.
본 발명에서 유효성분으로 사용하는 실데나필 시트레이트염은 1정당 실데나필로써 25 내지 100 mg의 양을 함유하는 것이 좋다. 또한, 상기 이온교환수지는 전체 제형 중 10 내지 30 중량%, 바람직하게는 13 내지 20 중량%를 함유하고, 싸이클로덱스트린은 전체 제형 중 5 내지 40 중량%, 바람직하게는 10 내지 20 중량%를 함유하는 것이 좋다. The sildenafil citrate salt used as an active ingredient in the present invention may contain 25 to 100 mg of sildenafil per tablet. In addition, the ion exchange resin contains 10 to 30% by weight, preferably 13 to 20% by weight of the total formulation, and cyclodextrin contains 5 to 40% by weight, preferably 10 to 20% by weight of the total formulation. Good to do.
다음으로 본 발명의 저작정은 상기 제형을 제조하기 위한 약제학적으로 허용가능한 담체로 해당분야에서 통상적으로 사용하는 당류, 결합제, 붕해제, 착향제, 감미제, 활택제 등을 함유한다.Next, the chewable tablet of the present invention contains a saccharide, a binder, a disintegrant, a flavoring agent, a sweetening agent, a lubricant, and the like, which are commonly used in the art as a pharmaceutically acceptable carrier for preparing the formulation.
상기 당류는 입안에서의 단맛, 용해성 및 촉감뿐만 아니라 유효성분의 용출, 흡수에 영향을 주는 중요한 성분으로 구강에서의 맛, 느낌 및 수용해도가 좋아야하며 입도 또한 이물감이 없어야할 정도로 작아야한다. 사용가능한 당류로는 유당, 만니톨, 솔비톨, 크실리톨, 에리스리톨, 글루코즈, 수크로즈, 과당, 레불로즈, 말토덱스트린, 파라티노즈 등이 있다. 상기 당류는 전체 제형 중 10 내지 70 중량%, 바람직하게는 20 내지 50 중량%를 함유하는 것이 좋다. The sugar is an important ingredient that affects the dissolution and absorption of the active ingredient, as well as sweetness, solubility, and touch in the mouth, and should have a good taste, feel, and water solubility in the oral cavity, and the mouth size should be small enough to be free from foreign substances. Sugars that can be used include lactose, mannitol, sorbitol, xylitol, erythritol, glucose, sucrose, fructose, rebulose, maltodextrin, paratinose and the like. The saccharide preferably contains 10 to 70% by weight, preferably 20 to 50% by weight of the total formulation.
상기 결합제는 본 발명의 저작정에서 강도를 나타내는데 필요한 성분으로 제품의 취급, 보관시 제품의 형상을 유지하는 목적으로 사용된다. 예컨데 폴리비닐피롤리돈, 비닐피롤리돈과 비닐아세테이트의 코폴리머, 히드록시프로필셀룰로오즈, 히드록시프로필메틸셀룰로오즈, 아라비아검, 크산탄검, 알긴산 나트륨, 수분산성 전분 및 유도체 등을 사용할 수 있으며 바람직하게는 히드록시프로필 셀룰로오즈를 사용하는 것이 좋다. 상기 결합제는 전체 제형 중 0.5 내지 20 중량%, 바람직하게는 1 내지 10 중량% 함유하는 것이 좋다. The binder is a component necessary to exhibit strength in the chewable tablet of the present invention and is used for the purpose of maintaining the shape of the product during handling and storage of the product. For example, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, hydroxypropylmethylcellulose, gum arabic, xanthan gum, sodium alginate, water-dispersible starch and derivatives may be used. For example, it is preferable to use hydroxypropyl cellulose. The binder is preferably contained 0.5 to 20% by weight, preferably 1 to 10% by weight of the total formulation.
상기 붕해제 성분은 본 발명의 저작정이 빠르게 붕해하기 위한 성분으로 유효성분의 용출, 흡수에 중요한 성분이다. 일반적으로 가교결합된 폴리비닐피롤리돈, 가교결합된 카르복시메칠셀룰로오스, 소디움 스타치 글리콜레이트, 칼슘 카르복시메틸셀룰로오스 등을 사용할 수 있으며 바람직하게는 가교결합된 카르복시메칠셀룰로오스를 사용하는 것이 좋다. 상기 붕해제는 전체 제형 중 0.5 내지 30 중량 %, 바람직하게는 2 내지 10 중량%를 함유하는 것이 좋다. The disintegrant component is a component for quickly disintegrating the chewable tablet of the present invention is an important component in the dissolution, absorption of the active ingredient. In general, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, sodium starch glycolate, calcium carboxymethyl cellulose, and the like may be used, and preferably cross-linked carboxymethyl cellulose is used. The disintegrant preferably contains 0.5 to 30% by weight, preferably 2 to 10% by weight of the total formulation.
또한 본 발명에 따른 저작정은 상기성분 외에도 본 발명의 효과를 해치지 않는 범위 내에서 예를 들어 스테아린산 마그네슘, 탈크, 스테아릴 푸마르산 나트륨 등의 활택제 성분과 아스파르탐, 스테비오사이드, 수크랄로오즈 등의 감미제, 딸기향 코톤, 블루베리향 코톤, 오렌지향 코톤 등의 착향제, 청색 1호, 황색 4호, 적색 2호 등의 착색제 등을 제제화를 돕기 위한 약제학적 첨가제로 추가로 포함할 수 있다. In addition, the chewable tablet according to the present invention, in addition to the above components in the range that does not impair the effects of the present invention, for example, lubricant components such as magnesium stearate, talc, sodium stearyl fumarate and aspartame, stevioside, sucralose Sweeteners, strawberry flavors, blueberry flavors, orange flavors such as flavoring agents, blue No. 1, yellow No. 4, red No. 2 and other colorants may be further included as a pharmaceutical additive to aid in formulating. .
상기와 같은 성분을 사용하여 저작정을 제조하였다. 제조과정 1은 A chewable tablet was prepared using the above ingredients. Manufacturing process 1
① 유효성분인 실데나필 시트레이트염과 이온교환수지, 베타-싸이클로덱스트린을 적당한 용매에서 반응시켜 쓴맛을 차폐시키는 단계① The step of masking bitter taste by reacting sildenafil citrate salt, ion exchange resin and beta-cyclodextrin as an active ingredient in a suitable solvent
② ①의 혼합물을 건조시키는 단계② drying the mixture of ①
③ 결합제를 용매에 녹여 결합액을 만드는 단계③ dissolving the binder in a solvent to form a binder solution
④ ②의 건조물을 정립 후 다른 부형제 및 ③의 결합액과 연합하는 단계④ After establishing the dried material of ② and the step of associating with other excipients and binding liquid of ③
⑤ 제립하여 과립으로 만드는 단계⑤ granules to make granules
⑥ ⑤의 과립물을 건조시키는 단계Step of drying the granules of ⑥ ⑤
⑦ 정립 후 감미제, 활택제 등과 후혼합하는 단계⑦ The step of post-mixing with sweetener, lubricant and etc. after formulation
⑧ 타정하는 단계를 거쳐 저작정을 제조하였다. ⑧ The chewable tablet was manufactured through the tableting step.
하지만 상기의 제조과정 1을 따라 제조시 두 번의 건조 공정에 시간이 오래 걸려 제조 시간이 길어지고 차폐 및 제립 공정시 일어나는 원료의 손실로 인해 수득률이 낮은 문제점이 있다. 또한 정립시 압축이 일어나게 되는데 두 번의 정립으로 인해 일어난 압축으로 인해 용출률이 저하되는 단점이 발견되었다. However, according to the manufacturing process 1, there is a problem in that the yield is low due to the long drying time of the two drying processes and the loss of the raw materials during the shielding and granulation process. In addition, compression occurs during formulation, and the dissolution rate decreases due to compression caused by two formulations.
이에 발명자들은 차폐 공정 후 건조를 하지 않고 바로 제립 공정을 진행하는 방법으로 저작정을 제조하였다. 이 제조과정 2는Therefore, the inventors prepared a chewable tablet by a method of performing the granulation process immediately without drying after the shielding process. This manufacturing process 2
① 유효성분인 실데나필 시트레이트염과 이온교환수지, 베타-싸이클로덱스트린을 적당한 용매에서 반응시켜 쓴맛을 차폐시킴과 동시에 결합제를 첨가해 결합액을 만드는 단계① The step of reacting sildenafil citrate salt, ion exchange resin, and beta-cyclodextrin as an active ingredient in a suitable solvent to mask bitterness and adding a binder to make a binder solution
② 다른 부형제와 ①의 결합액을 연합하는 단계② The step of associating the binder solution of ① with other excipients
③ 제립하여 과립으로 만드는 단계,③ granulation to granules,
④ ③의 과립물을 건조시키는 단계,④ drying the granules of ③,
⑤ 정립 후 감미제, 활택제 등과 후혼합하는 단계, ⑤ post-mixing with sweeteners, glidants, etc.
⑥ 타정하는 단계를 거쳐 제조됐다. ⑥ It was manufactured by tableting.
하지만 제조과정 1에서는 차폐와 결합액에 쓰일 적당한 용매의 선택이 비교적 자유로운데 반해 상기 제조과정 2의 ①에서는 주성분의 차폐와 동시에 제립시 결합액으로 사용할 수 있는 용매가 선택되어야하기 때문에 용매의 종류와 양이 제한될 수밖에 없다. 또한 상기 제조과정 2를 따라 제조시 여전히 원하는 용출률에 도달하지 못한다. However, in the preparation process 1, the selection of a suitable solvent for the shielding and the bonding liquid is relatively free, whereas in the preparation process 2 ①, the solvent which can be used as the bonding liquid at the same time as the shielding of the main components should be selected. The amount is bound to be limited. In addition, when prepared according to the manufacturing process 2, it still does not reach the desired dissolution rate.
이에 발명자들은 제립공정을 진행하지 않고 차폐된 주성분과 이온교환수지, 베타-싸이클로덱스트린을 부형제들과 혼합 후 바로 타정하는 방법으로 저작정을 제조하였다. 이 제조과정 3은 Therefore, the inventors prepared a chewable tablet by mixing the shielded main component, ion exchange resin, and beta-cyclodextrin with excipients without tableting. This manufacturing process 3
① 유효성분인 실데나필 시트레이트염과 이온교환수지, 베타-싸이클로덱스트린을 적당한 용매에서 반응시켜 쓴맛을 차폐시키는 단계① The step of masking bitter taste by reacting sildenafil citrate salt, ion exchange resin and beta-cyclodextrin as an active ingredient in a suitable solvent
② ①의 혼합물을 건조시키는 단계② drying the mixture of ①
③ 정립 후 다른 부형제들과 혼합하는 단계③ After formulation, mixing with other excipients
④ 타정하는 단계를 거쳐 저작정을 제조하였다. ④ A chewable tablet was prepared by the step of tableting.
상기 제조과정 3의 방법은 높은 수득률을 보였으며 우수한 용출률을 보였다. The process of Preparation 3 showed high yield and excellent dissolution rate.
아래에서 실시예를 들어 본 발명을 더욱 상세히 설명하나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 아래에서 상술하는 실시예들에 한정되는 것으로 해석되어서는 안 된다.Hereinafter, the present invention will be described in more detail with reference to Examples, but embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should be construed as being limited to the embodiments described below. Can not be done.
실시예 1Example 1
하기 표 1에 기재된 성분과 함량으로 실데나필 시트레이트의 저작정을 제조과정 3을 따라 제조하였다. 실데나필 시트레이트와 폴아크릴린 포타슘, 베타-싸이클로덱스트린을 교반기를 사용해 정제수 (1정당 0.5g)에 분산시키고 차폐를 한다. 8시간 방치 후 50℃에서 건조시킨다. 건조시킨 후 20호체로 정립하고 만니톨, 히드록시프로필셀룰로오스, 크로스카멜로오스 소디움, 스테비오사이드, 블루베리향 코톤, 스테아르산 마그네슘과 혼합하여 타정한다. 타정시 강도는 7 내지 12 KP이다. The chewable tablets of sildenafil citrate were prepared according to Preparation 3 using the ingredients and contents shown in Table 1 below. Sildenafil citrate, polyacrylic potassium and beta-cyclodextrin are dispersed in purified water (0.5 g per tablet) using a stirrer and shielded. It is left to stand for 8 hours and then dried at 50 ° C. After drying, the mixture was formed into a No. 20 sieve and mixed with mannitol, hydroxypropyl cellulose, croscarmellose sodium, stevioside, blueberry flavored coton, and magnesium stearate. The strength at the time of tableting is 7 to 12 KP.
실시예 2Example 2
각 성분의 중량이 하기 표 1에 표기된 것을 제외하고 제조방법은 실시예 1과 같다. Except that the weight of each component is shown in Table 1, the preparation method is the same as in Example 1.
표 1
구성 성분 함량 (mg)
실시예 1 실시예 2
실데나필 시트레이트 140.45 140.45
폴아크릴린 포타슘 100.00 140.00
베타-싸이클로덱스트린 70.00 70.00
만니톨 247.55 207.55
히드록시프로필셀룰로오스 10.00 10.00
크로스카멜로오스 소디움 48.00 48.00
스테비오사이드 2.00 2.00
블루베리향 코톤 2.00 2.00
스테아르산 마그네슘 14.00 14.00
총 중량 634.00 634.00
Table 1
Component Content (mg)
Example 1 Example 2
Sildenafil Citrate 140.45 140.45
Polyacrylic potassium 100.00 140.00
Beta-cyclodextrin 70.00 70.00
Mannitol 247.55 207.55
Hydroxypropyl cellulose 10.00 10.00
Croscarmellose Sodium 48.00 48.00
Stevioside 2.00 2.00
Blueberry Flavored Coton 2.00 2.00
Magnesium stearate 14.00 14.00
Total weight 634.00 634.00
비교예 1~7Comparative Examples 1-7
각 성분의 중량이 하기 표 2에 표기된 것을 제외하고 제조방법은 실시예 1과 같다. Except that the weight of each component is shown in Table 2, the preparation method is the same as in Example 1.
표 2
구성 성분 함량 (mg)
비교예 1 비교예 2 비교예 3 비교예 4 비교예 5 비교예 6 비교예 7
실데나필 시트레이트 140.45 140.45 140.45 140.45 140.45 140.45 140.45
폴아크릴린 포타슘 - - - - 70.00 100.00 140.00
베타-싸이클로덱스트린 - 70.00 140.00 210.00 - - -
만니톨 417.55 347.55 277.55 207.55 347.55 317.55 277.55
히드록시프로필셀룰로오스 10.00 10.00 10.00 10.00 10.00 10.00 10.00
크로스카멜로오스 소디움 48.00 48.00 48.00 48.00 48.00 48.00 48.00
스테비오사이드 2.00 2.00 2.00 2.00 2.00 2.00 2.00
블루베리향 코톤 2.00 2.00 2.00 2.00 2.00 2.00 2.00
스테아르산 마그네슘 14.00 14.00 14.00 14.00 14.00 14.00 14.00
총 중량 634.00 634.00 634.00 634.00 634.00 634.00 634.00
TABLE 2
Component Content (mg)
Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7
Sildenafil Citrate 140.45 140.45 140.45 140.45 140.45 140.45 140.45
Polyacrylic potassium - - - - 70.00 100.00 140.00
Beta-cyclodextrin - 70.00 140.00 210.00 - - -
Mannitol 417.55 347.55 277.55 207.55 347.55 317.55 277.55
Hydroxypropyl cellulose 10.00 10.00 10.00 10.00 10.00 10.00 10.00
Croscarmellose Sodium 48.00 48.00 48.00 48.00 48.00 48.00 48.00
Stevioside 2.00 2.00 2.00 2.00 2.00 2.00 2.00
Blueberry flavored cotton 2.00 2.00 2.00 2.00 2.00 2.00 2.00
Magnesium stearate 14.00 14.00 14.00 14.00 14.00 14.00 14.00
Total weight 634.00 634.00 634.00 634.00 634.00 634.00 634.00
비교예 8 Comparative Example 8
상기 표 1에 기재된 실시예 1과 같은 성분과 함량으로 실데나필 시트레이트염의 저작정을 제조과정 1을 따라 제조하였다. 실데나필 시트레이트와 폴아크릴린 포타슘, 베타-싸이클로덱스트린을 교반기를 사용해 정제수 (1정당 0.5g)에 분산시키고 차폐를 한다. 8시간 방치 후 50 ℃에서 건조시킨다. A chewable tablet of sildenafil citrate salt was prepared according to Preparation Process 1, using the same ingredients and contents as in Example 1 described in Table 1. Sildenafil citrate, polyacrylic potassium and beta-cyclodextrin are dispersed in purified water (0.5 g per tablet) using a stirrer and shielded. It is left to stand for 8 hours and then dried at 50 ° C.
건조시킨 후 20호체로 정립하고 만니톨, 절반의 크로스카멜로오스 소디움, 블루베리향 코톤을 혼합하고 히드록시프로필셀룰로오스를 정제수 (1정당 0.1g)에 녹인 결합액을 가해 연합한다. 과립기를 사용해 1.5 ф로 제립한 후 50 ℃에서 건조시킨 후 20호체로 정립하고 스테비오사이드, 스테아르산 마그네슘과 후혼합하여 타정한다. 타정시 강도는 7 내지 12 KP이다. After drying, the mixture was formed into a No. 20 sieve, mannitol, half croscarmellose sodium, and blueberry flavored cotons were mixed, and hydroxypropyl cellulose was dissolved in purified water (0.1 g per tablet) and added. Granules were granulated to 1.5 ф using a granulator, then dried at 50 ° C., sieved to No. 20, and then mixed with stevioside and magnesium stearate and compressed into tablets. The strength at the time of tableting is 7 to 12 KP.
비교예 9 Comparative Example 9
각 성분의 중량이 상기 표 1에 표기된 실시예 2와 같은 것을 제외하고 제조방법은 비교예 8과 같다. Except that the weight of each component is the same as in Example 2 shown in Table 1, the manufacturing method is the same as in Comparative Example 8.
비교예 10 Comparative Example 10
상기 표 1에 기재된 실시예 1과 같은 성분과 함량으로 실데나필 시트레이트염의 저작정을 제조과정 2를 따라 제조하였다. 실데나필 시트레이트와 폴아크릴린 포타슘, 베타-싸이클로덱스트린을 교반기를 사용해 80% 에탄올 (w/w, 1정당 0.35g)에 분산시키고 차폐를 하고 히드록시프로필셀룰로오스를 첨가해 결합액을 만든다. 8시간 방치 후 만니톨, 절반의 크로스카멜로오스 소디움, 블루베리향 코톤을 혼합한 혼합물에 결합액을 가해 연합한다. 과립기를 사용해 1.5 ф로 제립한 후 50 ℃에서 건조시킨 후 20호체로 정립하고 스테비오사이드, 스테아르산 마그네슘과 후혼합하여 타정한다. 타정시 강도는 7 내지 12 KP이다. A chewable tablet of sildenafil citrate salt was prepared in Preparation Process 2, using the same ingredients and contents as in Example 1, described in Table 1. Sildenafil citrate, polyacrylic potassium and beta-cyclodextrin are dispersed in 80% ethanol (w / w, 0.35 g per tablet) using a stirrer, shielded and hydroxypropylcellulose is added to form a binding solution. After 8 hours, the binding solution is added to the mixture of mannitol, half croscarmellose sodium and blueberry flavored coton. Granules were granulated to 1.5 ф using a granulator, then dried at 50 ° C., sieved to No. 20, and then mixed with stevioside and magnesium stearate and compressed into tablets. The strength at the time of tableting is 7 to 12 KP.
비교예 11Comparative Example 11
각 성분의 중량이 상기 표 1에 표기된 실시예 2와 같은 것을 제외하고 제조방법은 비교예 10과 같다. Except that the weight of each component is the same as in Example 2 shown in Table 1, the manufacturing method is the same as in Comparative Example 10.
실험예 1 : 조성에 따른 차폐 효과 비교 Experimental Example 1 Comparison of Shielding Effect According to Composition
표 3
실시예 1 실시예 2 비교예 1 비교예 2 비교예 3 비교예 4 비교예 5 비교예 6 비교예 7
쓴 맛 차폐 정도 5 5 1 2 2 3 3 4 4
TABLE 3
Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7
Bitter taste shielding degree 5 5 One 2 2 3 3 4 4
(1 : 쓴맛 차폐 없음, 2 : 쓴맛 조금 차폐, 3 : 쓴맛 보통 차폐 4 : 쓴맛 많이 차폐 5 : 쓴맛 완전 차폐)(1: no bitterness shielding, 2: bitter little shielding, 3: bitterness normal shielding 4: masking a lot of bitter taste 5: complete shielding bitterness)
실험예 2 : 제조과정에 따른 수득률 비교 Experimental Example 2 Comparison of Yields According to Manufacturing Process
표 4
실시예 1 실시예 2 비교예 8 비교예 9 비교예 10 비교예 11
수득률 (%)(5000정 제조시) 97.8 97.1 87.2 86.4 92.1 91.3
Table 4
Example 1 Example 2 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11
Yield (%) (when manufacturing 5000 tablets) 97.8 97.1 87.2 86.4 92.1 91.3
실험예 3 : 용출률 비교 시험 Experimental Example 3 Dissolution Rate Comparison Test
실데나필 시트레이트염의 용출 시험은 아래 조건과 같이 실시하였다. The dissolution test of sildenafil citrate salt was carried out as follows.
· 온도 : 37 ± 0.5 ℃Temperature: 37 ± 0.5 ℃
· 용출법 : 대한약전 용출시험 제 1법(Basket 법)Dissolution method: Method 1 of dissolution test of Korea Pharmacopoeia (Basket method)
· 용출액 : 0.1 N HCl, 900 mLEluent: 0.1 N HCl, 900 mL
· 교반 속도 : 100 RPMStirring Speed: 100 RPM
· 분석 방법 : 액체크로마토그래프Analysis method: liquid chromatograph
Column : Mobile phase : 0.05M 인산트리에칠아민 (pH=3.0):메탄올:아세토니트릴=580:250:170(v/v/v)Column: Mobile phase: 0.05M triethylamine phosphate (pH = 3.0): methanol: acetonitrile = 580: 250: 170 (v / v / v)
UV wavelength : 290nmUV wavelength: 290 nm
Flow rate : 1.0 mL/minFlow rate: 1.0 mL / min
Injection volume : 20 ㎕Injection volume: 20 μl
표 5
용출시간 (분)
0 5 10 15 30
용출률 (%) 실시예 1 0 88.2 98.5 99.2 99.9
실시예 2 0 89.1 98.4 99.6 99.7
비교예 1 0 71.4 90.9 98.4 99.7
비교예 2 0 85.1 97.3 99.1 99.9
비교예 3 0 87.3 97.9 99.0 99.4
비교예 4 0 87.2 98.2 98.7 99.5
비교예 5 0 76.3 95.9 98.5 98.7
비교예 6 0 72.5 92.4 97.5 99.5
비교예 7 0 70.9 91.2 97.7 99.0
비교예 8 0 45.4 80.4 90.4 97.7
비교예 9 0 47.1 80.2 89.7 98.6
비교예 10 0 61.6 87.1 93.8 98.2
비교예 11 0 59.1 84.2 91.7 99.1
Table 5
Dissolution time (minutes)
0 5 10 15 30
Dissolution rate (%) Example 1 0 88.2 98.5 99.2 99.9
Example 2 0 89.1 98.4 99.6 99.7
Comparative Example 1 0 71.4 90.9 98.4 99.7
Comparative Example 2 0 85.1 97.3 99.1 99.9
Comparative Example 3 0 87.3 97.9 99.0 99.4
Comparative Example 4 0 87.2 98.2 98.7 99.5
Comparative Example 5 0 76.3 95.9 98.5 98.7
Comparative Example 6 0 72.5 92.4 97.5 99.5
Comparative Example 7 0 70.9 91.2 97.7 99.0
Comparative Example 8 0 45.4 80.4 90.4 97.7
Comparative Example 9 0 47.1 80.2 89.7 98.6
Comparative Example 10 0 61.6 87.1 93.8 98.2
Comparative Example 11 0 59.1 84.2 91.7 99.1
실험예의 결과를 비교해보면, 폴아크릴린 포타슘과 베타-싸이클로덱스트린을을 사용하여 저작정을 제조한 실시예 1 및 실시예 2는 쓴맛이 완전히 차폐되었으며, 수득률에서는 97%로 높은 수치를 나타내였고, 용출률에서도 비교예에 비해 높은 수치를 나타내었다. Comparing the results of the experimental example, Example 1 and Example 2 prepared by chewing tablet using polyacrylic potassium and beta-cyclodextrin was completely masked bitter taste, the yield was high as 97%, The dissolution rate was also higher than that of the comparative example.
따라서 본 발명에 의해 제조된 실데나필 시트레이트염의 저작정은 용출의 신속함과 쓴맛이 마스킹측면에서 우수하고, 복용이 간편하므로 환자에게 투여시 매우 유용할 것으로 기대된다.Therefore, the chewable tablets of sildenafil citrate salt prepared according to the present invention are expected to be very useful when administered to a patient because of the quickness of dissolution and bitter taste in terms of masking and ease of taking.

Claims (5)

  1. 카르복실기를 가지는 이온교환수지를 사용하여 쓴맛을 차폐한 후, 싸이클로덱스트린을 추가로 사용하여 쓴맛을 차폐한 실데나필 시트레이트 저작정.Sildenafil citrate chewable tablets having a bitter taste masked by further using cyclodextrin after using an ion exchange resin having a carboxyl group.
  2. 제 1항에 있어서, The method of claim 1,
    유당, 만니톨, 솔비톨, 크실리톨, 에리스리톨, 글루코즈, 수크로즈, 과당, 레불로즈, 말토덱스트린 및 파라티노즈로 이루어진 군에서 선택된 1종 또는 2종 이상의 첨가제를 저작정 전체중량의 10 내지 70 중량% 로 포함하는 것을 특징으로 하는 실데나필 시트레이트 저작정.Lactose, mannitol, sorbitol, xylitol, erythritol, glucose, sucrose, fructose, levose, maltodextrin and paratinose, one or two or more additives selected from the group of 10 to 70 weight Sildenafil citrate chewable tablets comprising as a%.
  3. 제 1항에 있어서, The method of claim 1,
    폴리비닐피롤리돈, 비닐피롤리돈과 비닐아세테이트의 코폴리머, 히드록시프로필셀룰로오즈, 히드록시프로필메틸셀룰로오즈, 아라비아검, 크산탄검, 알긴산 나트륨 및 수분산성 전분으로 이루어진 군에서 선택된 1종 또는 2종 이상의 결합제를 저작정 전체중량의 0.5 내지 20 중량% 로 포함하는 것을 특징으로 하는 실데나필 시트레이트 저작정.One or two selected from the group consisting of polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, hydroxypropylmethylcellulose, gum arabic, xanthan gum, sodium alginate and water dispersible starch Sildenafil citrate chewable tablet comprising at least 0.5 binder in an amount of 0.5 to 20% by weight of the total weight of chewable tablet.
  4. 제 1항에 있어서, The method of claim 1,
    가교결합된 폴리비닐피롤리돈, 가교결합된 카르복시메칠셀룰로오스, 소디움 스타치 글리콜레이트 및 칼슘 카르복시메틸셀룰로오스로 이루어진 군에서 선택된 1종 또는 2종 이상의 붕해제를 저작정 전체중량의 0.5 내지 30 중량% 로 포함하는 것을 특징으로 하는 실데나필 시트레이트 저작정.0.5 to 30% by weight of the total weight of the chewing tablet with one or two or more disintegrants selected from the group consisting of crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, sodium starch glycolate and calcium carboxymethylcellulose Sildenafil citrate chewable tablets, characterized in that it comprises a.
  5. 유효성분인 실데나필 시트레이트염, 이온교환수지 및 싸이클로덱스트린을 용매에서 반응시켜 쓴 맛을 차폐한 공정 후 별도의 공정을 거치지 않고 혼합 후 바로 타정하는 실데나필 시트레이트 저작정의 제조방법.A method for preparing sildenafil citrate chewable tablets, which is prepared by mixing the active ingredients sildenafil citrate salt, ion exchange resin, and cyclodextrin in a solvent, and then mixing them immediately after mixing without masking the bitter taste.
PCT/KR2012/006856 2011-11-25 2012-08-28 Chewable sildenafil citrate tablets in which bitterness is masked, and production method therefor WO2013077533A1 (en)

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KR101878599B1 (en) * 2017-03-28 2018-07-13 전북대학교산학협력단 Coprecipitation composition for accelerating the absorption and adjustment of the taste of methyl sulfonyl methanemannitol and its preparation method

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