KR20230065222A - Pharmaceutical composition comprising solifenacin or its pharmaceutically acceptable salts - Google Patents
Pharmaceutical composition comprising solifenacin or its pharmaceutically acceptable salts Download PDFInfo
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- KR20230065222A KR20230065222A KR1020230057100A KR20230057100A KR20230065222A KR 20230065222 A KR20230065222 A KR 20230065222A KR 1020230057100 A KR1020230057100 A KR 1020230057100A KR 20230057100 A KR20230057100 A KR 20230057100A KR 20230065222 A KR20230065222 A KR 20230065222A
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- drug layer
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- plasticizer
- core layer
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- 150000003839 salts Chemical class 0.000 title claims abstract description 32
- 229960003855 solifenacin Drugs 0.000 title claims abstract description 31
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- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
본 발명은 코어층(1) 및 상기 코어층(1) 위에 코팅된 약물층(2)을 포함하고, 상기 약물층(2)은 솔리페나신 또는 이의 약제학적으로 허용가능한 염 및 가소제를 함유하는 약제학적 조성물을 제공한다. 또한, 본 발명은 상기 약제학적 조성물을 포함하는 약제학적 제제, 특히 구강붕해정을 제공한다. 본 발명의 약제학적 조성물은 쓴맛을 차폐하고, 유연물질의 발생을 최소화하여 유효성분의 안정성을 확보할 수 있는 효과를 나타낸다. 또한, 본 발명의 약제학적 제제는 구강붕해정으로서 고령 환자의 복약순응도를 크게 개선하면서 기존 제제와 비교하여 동등한 약리효과를 달성할 수 있다.The present invention includes a core layer (1) and a drug layer (2) coated on the core layer (1), wherein the drug layer (2) contains solifenacin or a pharmaceutically acceptable salt thereof and a plasticizer. A pharmaceutical composition is provided. In addition, the present invention provides a pharmaceutical preparation, particularly an orally disintegrating tablet comprising the above pharmaceutical composition. The pharmaceutical composition of the present invention has the effect of securing the stability of active ingredients by masking bitter taste and minimizing generation of related substances. In addition, the pharmaceutical formulation of the present invention, as an orally disintegrating tablet, can achieve equivalent pharmacological effects compared to existing formulations while significantly improving the medication compliance of elderly patients.
Description
본 발명은 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 함유하는 약제학적 조성물에 관한 것이다. 더불어, 본 발명은 상기 약제학적 조성물을 포함하는 약제학적 제제, 특히 구강붕해정에 관한 것이다. The present invention relates to a pharmaceutical composition containing solifenacin or a pharmaceutically acceptable salt thereof. In addition, the present invention relates to a pharmaceutical formulation, particularly an orally disintegrating tablet comprising the above pharmaceutical composition.
솔리페나신은 하기 화학식 I 로 표시되는 화합물로서, 무스카린 M3 수용체에 대한 우수한 선택적 길항작용을 나타내며 절박성 뇨실금, 빈뇨 요절박과 같은 과민성 방광 치료제로 잘 알려져 있다.Solifenacin is a compound represented by Formula I below, and exhibits excellent selective antagonism to the muscarinic M3 receptor and is well known as a treatment for overactive bladder such as urge urinary incontinence and urinary urgency.
[화학식 I][Formula I]
과민성 방광과 같은 배뇨 장애는 삼키기가 어려운 고령 환자에서 많기 때문에 일반적인 정제 및 캡슐제보다는 구강 내에서 신속하게 붕해될 수 있는 정제(예를 들면, 구강붕해정)가 복용시 편의성 및 순응도 향상 면에서 바람직하다. 더욱이 야간 빈뇨 등에는 약과 물을 함께 섭취하는데 부담이 있어 환자들도 물 없이 먹는 구강붕해정에 대한 선호도가 매우 높은 편이다.. 따라서, 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 포함하는 구강붕해제 개발에 대한 상당한 니즈가 있다.Since urination disorders such as overactive bladder are common in elderly patients who have difficulty swallowing, tablets that can quickly disintegrate in the oral cavity (eg, orally disintegrating tablets) are preferable in terms of convenience and compliance when taking them rather than general tablets and capsules. . Furthermore, since it is burdensome to take medicine and water together for nocturia, etc., patients also have a very high preference for oral disintegrating tablets to be taken without water. Therefore, oral cavity containing solifenacin or a pharmaceutically acceptable salt thereof. There is a significant need for the development of disintegrants.
그런데, 솔리페나신 또는 이의 약제학적으로 허용가능한 염은 매우 강한 쓴맛을 갖는 것으로 알려져 있다. 따라서, 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 포함하는 구강붕해정을 개발하기 위해서는, 환자의 복약순응도를 높이기 위하여 쓴맛을 차폐하는 제제학적 조절이 필요하다.By the way, solifenacin or a pharmaceutically acceptable salt thereof is known to have a very strong bitter taste. Therefore, in order to develop an orally disintegrating tablet containing solifenacin or a pharmaceutically acceptable salt thereof, it is necessary to adjust the pharmaceutical preparation to mask the bitter taste in order to increase patient compliance.
한편 대한민국 공개특허공보 제10-2007-0098889호에는, 쓴맛을 차단한 과립상 물질을 수득하기 위해서 코어 입자에 약물 용액을 분무하여 미립자를 제조할 때 솔리페나신 또는 그의 염을 용액에 용해시켜 분무해야 하는데, 이때 솔리페나신은 결정형으로 변화되기 쉽고 무정형에서 결정형으로 변화될 때 분해물이 생성되기 때문에 솔리페나신을 용매에 용해시켜 과립상 물질을 수득하는 경우 솔리페나신의 안정성을 확보할 수 없다고 기재되어 있다. Meanwhile, Korean Patent Publication No. 10-2007-0098889 discloses that, in order to obtain a granular material with a bitter taste, solifenacin or a salt thereof is dissolved in a solution and sprayed when preparing microparticles by spraying a drug solution on core particles. At this time, since solifenacin is easily changed into a crystalline form and a degradant is generated when changing from an amorphous form to a crystalline form, it is described that the stability of solifenacin cannot be secured when a granular material is obtained by dissolving solifenacin in a solvent. .
따라서, 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 포함하는 제제의 제조에 있어서 솔리페나신의 안정성 확보도 매우 중요한 문제이다. 특히, 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 포함하는 구강붕해정의 제조시 타정에 의한 펠렛의 손상 가능성이 있으며, 이로 인하여 쓴맛 차폐가 실패할 위험이 있다.Therefore, securing the stability of solifenacin is also a very important issue in the preparation of a formulation containing solifenacin or a pharmaceutically acceptable salt thereof. In particular, when preparing an orally disintegrating tablet containing solifenacin or a pharmaceutically acceptable salt thereof, there is a possibility of damage to the pellet by tableting, and thereby there is a risk of bitter taste masking failure.
본 발명의 목적은 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 쓴맛을 효과적으로 차폐할 수 있고 유연물질의 발생을 최소화하여 유효성분의 안정성도 확보할 수 있는 약제학적 조성물 및 이의 제조방법을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition capable of effectively masking the bitter taste of solifenacin or a pharmaceutically acceptable salt thereof and securing the stability of active ingredients by minimizing the generation of related substances, and a method for preparing the same. will be.
본 발명의 다른 목적은 쓴맛을 차폐하여 연하력이 약한 고령 환자의 복약순응도를 개선하면서 기존 제제와 비교하여 동등한 약리효과를 달성할 수 있는 솔리페나신 또는 이의 약제학적으로 허용가능한 염의 약제학적 제제를 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical preparation of solifenacin or a pharmaceutically acceptable salt thereof capable of achieving equivalent pharmacological effects compared to existing preparations while improving the medication compliance of elderly patients with weak swallowing ability by masking the bitter taste. is to provide
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.A detailed description of this is as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific descriptions described below.
솔리페나신 또는 이의 약제학적으로 허용가능한 염을 함유하는 약제학적 조성물, 및 이의 제조방법Pharmaceutical composition containing solifenacin or a pharmaceutically acceptable salt thereof, and method for preparing the same
본 발명은 코어층(1) 및 상기 코어층(1) 위에 코팅된 약물층(2)을 포함하고, 상기 약물층(2)은 솔리페나신 또는 이의 약제학적으로 허용가능한 염 및 가소제를 함유하는 약제학적 조성물을 제공한다. 상기 가소제는 트리아세틴, 프로필렌글리콜, 폴리에틸렌글리콜, 시트르산트리에틸, 글리세린, 디부틸세바케이트, 프탈산디에틸 및 이들의 혼합물로 이루어진 군으로부터 선택될 수 있다. 다만 이에 제한되지 않는다. The present invention includes a core layer (1) and a drug layer (2) coated on the core layer (1), wherein the drug layer (2) contains solifenacin or a pharmaceutically acceptable salt thereof and a plasticizer. A pharmaceutical composition is provided. The plasticizer may be selected from the group consisting of triacetin, propylene glycol, polyethylene glycol, triethyl citrate, glycerin, dibutyl sebacate, diethyl phthalate, and mixtures thereof. However, it is not limited thereto.
본 발명의 일 실시양태에 따르면, 상기 약물층(2) 위에 코팅 기제로 코팅되는 코팅층(3)을 더 포함할 수 있다.According to one embodiment of the present invention, a coating layer (3) coated with a coating base may be further included on the drug layer (2).
본 발명에서, 상기 코어층은 백당, 만니톨, 소르비톨, 유당, 감자전분, 옥수수전분, 히드록시에틸셀룰로오스, 미결정셀룰로오스, 백납, 카르나우바 왁스, 미결정 왁스 및 이들의 혼합물로 이루어진 군에서 선택된 물질일 수 있다. 바람직하게는, 상기 코어층으로 백당(슈가 스피어)를 사용할 수 있다.In the present invention, the core layer is a material selected from the group consisting of sucrose, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethyl cellulose, microcrystalline cellulose, white wax, carnauba wax, microcrystalline wax, and mixtures thereof can Preferably, white sugar (sugar spheres) may be used as the core layer.
본 발명에서 용어, "약제학적으로 허용가능한 염"은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 약리 활성성분의 이로운 효능을 저하시키지 않는 임의의 모든 유기 또는 무기 부가 염을 의미한다. 상기 약제학적으로 허용가능한 염은, 약학적으로 허용되는 산 또는 염기로부터 유도된 염을 포함한다. 상기 약제학적으로 허용 가능한 염의 제조에 사용될 수 있는 산은 무기산 또는 유기산일 수 있다. 무기산은 예컨대, 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있고, 유기산은 예컨대, 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있으나, 이에 제한되는 것은 아니다. 또한, 알라닌, 글라이신 등 천연 아미노산 등을 사용하여 제조된 아미노산 부가염기도 본 발명의 약학적으로 허용가능한 염에 포함될 수 있다. 또한, 상기 약제학적으로 허용 가능한 염의 제조에 사용될 수 있는 염기는 예컨대, 트리스(히드록시메틸)메틸아민, 디시클로헥실아민 등일 수 있으나, 이에 제한되는 것은 아니다. 본 발명에 있어서, 솔리페나신 숙신산염(숙시네이트)가 바람직하다. In the present invention, the term "pharmaceutically acceptable salt" is a concentration that has a relatively non-toxic and harmless effective effect on patients, and any organic or inorganic side effects caused by the salt do not reduce the beneficial efficacy of the pharmacologically active ingredient. means addition salt. The pharmaceutically acceptable salt includes a salt derived from a pharmaceutically acceptable acid or base. Acids that may be used for preparing the pharmaceutically acceptable salts may be inorganic acids or organic acids. Inorganic acids, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc. may be used, and organic acids, for example, acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malic acid Lonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like may be used, but are not limited thereto. In addition, amino acid addition bases prepared using natural amino acids such as alanine and glycine may also be included in the pharmaceutically acceptable salts of the present invention. In addition, the base that can be used for preparing the pharmaceutically acceptable salt may be, for example, tris(hydroxymethyl)methylamine, dicyclohexylamine, etc., but is not limited thereto. In the present invention, solifenacin succinate (succinate) is preferred.
본 발명에 있어서, 상기 가소제로 트리아세틴, 프로필렌글리콜, 폴리에틸렌글리콜, 시트르산트리에틸, 글리세린, 디부틸세바케이트, 프탈산디에틸 및 이들의 혼합물로 이루어진 군으로부터 선택된 것을 사용함으로써, 타정에 의한 펠렛의 손상을 방지할 수 있으며 이를 통하여 쓴맛 차폐 효과를 달성할 수 있다.In the present invention, by using a plasticizer selected from the group consisting of triacetin, propylene glycol, polyethylene glycol, triethyl citrate, glycerin, dibutyl sebacate, diethyl phthalate and mixtures thereof, damage to the pellets by tableting can be prevented, and through this, the bitter taste shielding effect can be achieved.
또한 본 발명에 있어서, 상기 가소제는 약물층(2) 총 중량 기준 7 중량% 이상일 수 있다. 또한, 상기 가소제는 코어층(1) 및 약물층(2) 합산 중량 기준 3 중량% 이상일 수 있다. 더 나아가, 상기 가소제는 코어층(1), 약물층(2) 및 코팅층(3) 합산 중량 기준 2.5 중량% 이상일 수 있다. In addition, in the present invention, the plasticizer may be 7% by weight or more based on the total weight of the drug layer (2). In addition, the plasticizer may be 3% by weight or more based on the total weight of the core layer (1) and the drug layer (2). Furthermore, the plasticizer may be 2.5% by weight or more based on the total weight of the core layer 1, the drug layer 2 and the coating layer 3.
본 발명의 일 실시양태에 따르면, 상기 약물층(2)은 결합제, 감미제 또는 항산화제를 더 함유할 수 있다. According to one embodiment of the present invention, the drug layer 2 may further contain a binder, sweetener or antioxidant.
본 발명에 있어서, 상기 결합제는 히드록시프로필메틸셀룰로오스(HPMC), 메틸셀룰로오스(Methyl cellulose), 폴리비닐피롤리돈(PVP), 산화에틸렌쇄를 갖는 물질, 히드록시에틸셀룰로오스, 에틸셀룰로오스, 폴리비닐알코올, 메타크릴산공중합체, 아미노알킬메타크릴레이트 공중합체, 전분 및 말토스로 이루어진 군에서 선택될 수 있다. 다만 이에 제한되지 않는다. In the present invention, the binder is hydroxypropylmethylcellulose (HPMC), methylcellulose, polyvinylpyrrolidone (PVP), a material having an ethylene oxide chain, hydroxyethylcellulose, ethylcellulose, polyvinyl It may be selected from the group consisting of alcohol, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, starch and maltose. However, it is not limited thereto.
본 발명에 있어서, 상기 감미제는 수크랄로오스, 수크로오스, 글루코오스, 프룩토오스, 덱스트로오스, 락토오스, 글루시톨, 자일리톨, 글리신, D-페닐알라닌, D-트립토판, 아스파르탐 및 사카린으로 이루어진 군으로부터 선택될 수 있다. 다만 이에 제한되지 않는다. In the present invention, the sweetener is composed of sucralose, sucrose, glucose, fructose, dextrose, lactose, glucitol, xylitol, glycine, D-phenylalanine, D-tryptophan, aspartame and saccharin. can be selected from the group. However, it is not limited thereto.
본 발명에 있어서, 상기 항산화제는 소듐 시트레이트(Sodium citrate), 시트르산(Citric acid), 부틸화 히드록시아니솔(Butyl hydroxy anisole), 부틸화 히드록시톨루엔(Butylated hydroxy toluene), 프로필 갈레이트(Propyl gallate) 및 에틸렌디아민-N,N,N',N'-테트라아세트산(EDTA)로 이루어지는 군으로부터 선택될 수 있다. 다만, 이에 제한되지 않는다.In the present invention, the antioxidant is sodium citrate, citric acid, butylated hydroxy anisole, butylated hydroxy toluene, propyl gallate ( propyl gallate) and ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA). However, it is not limited thereto.
본 발명에 있어서, 상기 약물층 용액의 용매는 에탄올, 아세톤, 에탄올과 아세톤 혼합액, 또는 물을 사용할 수 있으며, 물을 사용하는 것이 바람직하다. 본 발명에서 용매로 물을 사용할 경우, 코팅 과정에서 정전기 현상의 미발생으로 코팅 효율이 개선되고, 펠렛의 안정성도 향상되는 것을 확인할 수 있다. In the present invention, the solvent of the drug layer solution may be ethanol, acetone, a mixture of ethanol and acetone, or water, and water is preferably used. In the present invention, when water is used as a solvent, it can be seen that the coating efficiency is improved and the stability of the pellets is also improved due to the non-occurrence of static electricity during the coating process.
본 발명에서, 상기 코팅층(3)에 사용되는 코팅 기제는 메타크릴산 공중합체일 수 있다. 바람직하게는 유드라짓(Eudragit)을 사용할 수 있다. 구체적으로, 메타아크릴산부틸-(2-디메틸아미노에틸)메타아크릴산-메타아크릴산1:2:1 공중합체(Eudragit E), 메타아크릴산-메타아크릴산메틸 1:1(Eudragit L), 아크릴산에틸-메타아크릴산메틸-트리메틸암모니오에틸메타아크릴산클로라이드 1:2:0.2 공중합체(Eudragit RL), 아크릴산에틸-메타아크릴산메틸-트리메틸암모니오에틸메타아크릴산클로라이드 1:2:0.1 공중합체(Eudragit RS), 아크릴산에틸-메타아크릴산메틸 2:1 공중합체(Eudragit NE 또는 Eudragit NM), 및 이들의 혼합물을 사용할 수 있고, 바람직하게는 아크릴산에틸-메타아크릴산메틸 2:1 공중합체(Eudragit NE30D, Eudragit NE40D, 또는 Eudragit NM30D), 메타아크릴산-아크릴산에틸 1:1 공중합체(Eudragit L30-D55 또는 Eudragit L100-55), 및 이들의 혼합물을 사용할 수 있으며, 더욱 바람직하게는 아크릴산에틸-메타아크릴산메틸 2:1 공중합체(Eudragit NE30D), 메타아크릴산-아크릴산에틸 1:1 공중합체(Eudragit L30-D55), 및 이들의 혼합물을 사용할 수 있고, 가장 바람직하게는 아크릴산에틸-메타아크릴산메틸 2:1 공중합체(Eudragit NE30D) 및 메타아크릴산-아크릴산에틸 1:1 공중합체(Eudragit L30-D55)의 혼합물을 사용할 수 있다. 이 때 아크릴산에틸-메타아크릴산메틸 2:1(Eudragit NE30D) 및 메타아크릴산-아크릴산에틸 1:1 공중합체(Eudragit L30-D55)의 비율은 0.1:1 내지 3:1일 수 있으며, 바람직하게는 0.5 내지 2:1일 수 있고, 응집현상과 Twinning 현상을 경감시키고 쓴맛 및 이물감을 개선할 수 있다. In the present invention, the coating base used for the coating layer 3 may be a methacrylic acid copolymer. Preferably, Eudragit can be used. Specifically, butyl methacrylate-(2-dimethylaminoethyl)methacrylic acid-methacrylic acid 1:2:1 copolymer (Eudragit E), methacrylic acid-methyl methacrylate 1:1 (Eudragit L), ethyl acrylate-methacrylic acid Methyl-trimethylammonioethyl methacrylate 1:2:0.2 copolymer (Eudragit RL), ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate 1:2:0.1 copolymer (Eudragit RS), ethyl acrylate- Methyl methacrylate 2:1 copolymer (Eudragit NE or Eudragit NM), and mixtures thereof can be used, preferably ethyl acrylate-methyl methacrylate 2:1 copolymer (Eudragit NE30D, Eudragit NE40D, or Eudragit NM30D) , methacrylic acid-ethyl acrylate 1: 1 copolymer (Eudragit L30-D55 or Eudragit L100-55), and mixtures thereof may be used, more preferably ethyl acrylate-methyl methacrylate 2: 1 copolymer (Eudragit NE30D ), methacrylic acid-ethyl acrylate 1:1 copolymer (Eudragit L30-D55), and mixtures thereof, most preferably ethyl acrylate-methyl methacrylate 2:1 copolymer (Eudragit NE30D) and methacrylic acid - A mixture of ethyl acrylate 1:1 copolymer (Eudragit L30-D55) can be used. At this time, the ratio of ethyl acrylate-methyl methacrylate 2:1 (Eudragit NE30D) and methacrylic acid-ethyl acrylate 1:1 copolymer (Eudragit L30-D55) may be 0.1:1 to 3:1, preferably 0.5 to 2:1, reducing aggregation and twinning, and improving bitter taste and foreign body sensation.
본 발명의 약제학적 조성물은 펠렛, 과립제, 캡슐제, 정제, 산제, 현탁제 등과 같은 다양한 형태의 경구 제제로 제제화될 수 있다. 바람직하게는 펠렛일 수 있다. The pharmaceutical composition of the present invention may be formulated into various forms of oral preparations such as pellets, granules, capsules, tablets, powders, suspensions, and the like. Pellets may be preferred.
본 발명의 약제학적 조성물이 펠렛인 경우, 입자 크기가 50 내지 200 μm, 바람직하게는 80 내지 170 μm일 수 있다. 입자 크기가 위 범위일 때, 복용시 이물감이 적다. When the pharmaceutical composition of the present invention is a pellet, the particle size may be 50 to 200 μm, preferably 80 to 170 μm. When the particle size is within the above range, there is little foreign body sensation when taking.
또한, 본 발명은 위에서 언급한 약제학적 조성물의 제조방법을 제공한다. 구체적으로, 상기 제조방법은 (S-1) 솔리페나신 또는 이의 약제학적 허용가능한 염 및 가소제를 함유하는 약물층 용액을 코어층(1)에 분무하여 코팅하는 단계; 및 (S-2) 코팅 기제를 함유하는 용액을 상기 약물층(2)에 분무하여 코팅하는 단계를 포함한다. In addition, the present invention provides a method for preparing the above-mentioned pharmaceutical composition. Specifically, the manufacturing method includes (S-1) spraying and coating a drug layer solution containing solifenacin or a pharmaceutically acceptable salt thereof and a plasticizer on the core layer (1); and (S-2) coating the drug layer 2 by spraying a solution containing a coating base.
본 발명의 제조방법에 있어서, 상기 약물층 용액은 항산화제를 더 포함할 수 있다. 상기 항산화제는 위에서 언급한 바와 같다.In the manufacturing method of the present invention, the drug layer solution may further include an antioxidant. The antioxidants are as mentioned above.
또한 본 발명의 제조방법에 있어서, 상기 약물층 용액의 용매는 에탄올, 아세톤, 에탄올과 아세톤 혼합액, 또는 물을 사용할 수 있다. 바람직하게는, 유기용매를 사용하지 않을 수 있고, 특히 물을 사용하는 것이 바람직하다. 본 발명에서 용매로 물을 사용할 경우, 코팅 과정에서 정전기 현상의 미발생으로 코팅 효율이 개선되고, 펠렛의 안정성도 향상되는 것을 확인할 수 있다. In addition, in the preparation method of the present invention, ethanol, acetone, a mixture of ethanol and acetone, or water may be used as a solvent for the drug layer solution. Preferably, an organic solvent may not be used, and it is particularly preferable to use water. In the present invention, when water is used as a solvent, it can be seen that the coating efficiency is improved and the stability of the pellets is also improved due to the non-occurrence of static electricity during the coating process.
솔리페나신 또는 이의 약제학적으로 허용가능한 염을 포함하는 약제학적 제제Pharmaceutical preparations containing solifenacin or a pharmaceutically acceptable salt thereof
본 발명은 위에서 언급한 본 발명의 약제학적 조성물을 포함하는 약제학적 제제를 제공한다.The present invention provides a pharmaceutical preparation comprising the above-mentioned pharmaceutical composition of the present invention.
본 발명의 약제학적 제제는 정제 또는 캡슐제와 같은 다양한 형태의 경구 제제로 제제화될 수 있다. 구체적으로, 본 발명의 약제학적 제제는 정제 중에서도 구강붕해정일 수 있다. 구강붕해정은 제제를 복용함에 있어 물을 섭취하지 않고 실질적으로 타액에 의해서만 1분 이내(바람직하게는 40초 이내)에 붕해되는 약학 제제를 의미한다. 본 발명의 약제학적 제제가 구강붕해제인 경우, 구강 내에서 신속하게 붕해될 수 있으므로 과민성 방광과 같은 배뇨 장애는 삼키기가 어려운 고령 환자들이 복용시 편의성 및 순응도를 크게 향상시킬 수 있다. 특히, 야간 빈뇨 등에는 약과 물을 함께 섭취하는데 부담이 있는 환자들도 물 없이 먹을 수 있어 복약순응도가 상당히 개선된다. The pharmaceutical formulation of the present invention may be formulated into oral formulations in various forms such as tablets or capsules. Specifically, the pharmaceutical formulation of the present invention may be an orally disintegrating tablet among tablets. An oral disintegrating tablet refers to a pharmaceutical preparation that is substantially disintegrated only by saliva within 1 minute (preferably within 40 seconds) without ingesting water when taking the preparation. When the pharmaceutical preparation of the present invention is an oral disintegrant, it can be rapidly disintegrated in the oral cavity, so it can greatly improve the convenience and compliance of elderly patients who have difficulty swallowing due to urination disorders such as overactive bladder. In particular, patients who are burdened with taking medicine and water together for nighttime urination can take it without water, which significantly improves medication compliance.
본 발명에서, 유효성분인 솔리페나신 또는 이의 약제학적으로 허용가능한 염은 복용 후 혈중최고농도에 도달할 때(Tmax)까지 약 5.5 시간 정도 소요되는 약물로, 구강 내에서 빠르게 분해된다고 하더라도 실제 흡수는 대부분 장에서 이루어진다는 점이 알려져 있다. 따라서, 본 발명의 약제학적 제제가 구강붕해정인 경우 솔리페나신 또는 이의 약제학적으로 허용가능한 염의 초반 용출률을 억제한다면 쓴맛 차폐 효과를 얻을 수 있으며, 대신 그 이후 위장관에서의 용출률을 회복한다면 기존 약제학적 제제와 동등한 약리학적 효과를 얻을 수 있다.In the present invention, solifenacin or a pharmaceutically acceptable salt thereof, which is an active ingredient, is a drug that takes about 5.5 hours to reach the highest blood concentration (Tmax) after administration, and even if it is quickly decomposed in the oral cavity, it is actually absorbed. It is known that most of this occurs in the intestine. Therefore, when the pharmaceutical preparation of the present invention is an orally disintegrating tablet, if the initial dissolution rate of solifenacin or a pharmaceutically acceptable salt thereof is suppressed, a bitter taste masking effect can be obtained, and instead, if the dissolution rate in the gastrointestinal tract is restored thereafter, the existing drug Pharmacological effects equivalent to those of medical preparations can be obtained.
본 발명의 일 실시양태에 따르면, 상기 약제학적 제제는 MUPS(Multiple Unit Pellet System)으로 설계될 수 있다. According to one embodiment of the present invention, the pharmaceutical formulation may be designed as a Multiple Unit Pellet System (MUPS).
이 때, MUPS 펠렛은 본 발명의 약제학적 제제의 총 중량 기준 40 중량% 이하일 수 있다. 위 범위를 벗어나는 경우, 쓴맛 차폐 효과가 감소하여 구강붕해정으로서 적합하지 않을 수 있다. At this time, the MUPS pellets may be 40% by weight or less based on the total weight of the pharmaceutical formulation of the present invention. If it is out of the above range, the bitter taste masking effect is reduced and may not be suitable as an orally disintegrating tablet.
본 발명의 일 실시양태에 따르면, 본 발명에 따른 약제학적 조성물(예를 들어, 펠렛)를 약학적으로 허용가능한 첨가제(예를 들어, 희석제 등)와 혼합한 후 타정함으로써 구강붕해정의 형태로 제제화시킬 수 있다.According to one embodiment of the present invention, the pharmaceutical composition (eg, pellets) according to the present invention is mixed with pharmaceutically acceptable additives (eg, diluent, etc.) and compressed into tablets to form an orally disintegrating tablet. can be formulated.
본 발명에서 구강붕해정의 경도가 1-5 kp, 바람직하게는 2-4 kp, 더욱 바람직하게는 3 kp이다. 이때 마손도가 낮고 붕해시간을 60초 이내로 조절할 수 있다.The hardness of the orally disintegrating tablet in the present invention is 1-5 kp, preferably 2-4 kp, more preferably 3 kp. At this time, the degree of wear is low and the disintegration time can be controlled within 60 seconds.
또한, 본 발명에서 상기 희석제는 자일리톨, 트레할로스, 소르비톨, 말토스, 소르비톨, 에리스리톨, 글루코스, 말티톨, 만니톨, 백당, 락토스 및 이의 수화물로 이루어진 군에서 선택될 수 있다. 다만, 이에 제한되지 않는다. In the present invention, the diluent may be selected from the group consisting of xylitol, trehalose, sorbitol, maltose, sorbitol, erythritol, glucose, maltitol, mannitol, white sugar, lactose, and hydrates thereof. However, it is not limited thereto.
본 발명의 구강붕해정은 상기 성분들 이외에도, 약제학적으로 허용 가능한 첨가제로서 통상적으로 사용되는 붕해제, 산미제, 향료, 활택제 및 이의 조합 등을 포함할 수 있으며, 감미제 또는 착색제를 더 포함할 수 있다.In addition to the above components, the orally disintegrating tablet of the present invention may include a disintegrant, an acidulant, a flavoring agent, a lubricant, and combinations thereof, which are commonly used as pharmaceutically acceptable additives, and may further include a sweetening agent or a coloring agent. can
본 발명에서, 상기 붕해제는 크로스포비돈, 소듐 스타치 글리콜레이트, 크로스카멜로오스 소듐, 저치환 히드록시프로필셀룰로오스, 전분, 알긴산 또는 그의 소듐염, 및 이들의 혼합물로 이루어진 군에서 선택될 수 있다. 다만, 이에 제한되지 않는다.In the present invention, the disintegrant may be selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or a sodium salt thereof, and mixtures thereof. However, it is not limited thereto.
본 발명에서, 상기 산미료는 무수시트르산, 타르타르산, 말산 등을 사용할 수 있으며, 상기 향료로는 페퍼민트향, 딸기향, 박하향 분말, 멘톨, 레몬향 분말, 오렌지향 분말 등을 사용할 수 있다. 다만 이에 제한되지 않는다. In the present invention, as the acidulant, anhydrous citric acid, tartaric acid, malic acid, etc. may be used, and as the flavoring agent, peppermint flavor, strawberry flavor, peppermint flavor powder, menthol, lemon flavor powder, orange flavor powder, or the like may be used. However, it is not limited thereto.
본 발명에서, 상기 활택제는 소듐 스테아릴 푸마레이트, 마그네슘 스테아레이트, 칼슘 스테아레이트, 백당, 지방산 스테아레이트, 자당지방산에스테르, 활석, 수소첨가된 식물성 오일, 고융점의 왁스, 글리세릴지방산 에스테르류, 글리세릴베헤네이트 및 이들의 혼합물로 이루어진 군에서 선택될 수 있다. 다만 이에 제한되지 않는다. In the present invention, the lubricant is sodium stearyl fumarate, magnesium stearate, calcium stearate, white sugar, fatty acid stearate, sucrose fatty acid ester, talc, hydrogenated vegetable oil, high melting point wax, glyceryl fatty acid esters , glyceryl behenate, and mixtures thereof. However, it is not limited thereto.
본 발명에서, 상기 감미제는 수크랄로오스, 수크로오스, 글루코오스, 프룩토오스, 덱스트로오스, 락토오스, 글루시톨, 자일리톨, 글리신, D-페닐알라닌, D-트립토판, 아스파르탐 및 사카린으로 이루어진 군으로부터 선택될 수 있다. 다만 이에 제한되지 않는다. In the present invention, the sweetener is selected from the group consisting of sucralose, sucrose, glucose, fructose, dextrose, lactose, glucitol, xylitol, glycine, D-phenylalanine, D-tryptophan, aspartame and saccharin. can be selected from. However, it is not limited thereto.
본 발명에서, 상기 착색제는 철 산화물 또는 티타늄 산화물일 수 있다. 다만 이에 제한되지 않는다. In the present invention, the colorant may be iron oxide or titanium oxide. However, it is not limited thereto.
본 발명의 약제학적 조성물은 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 쓴맛을 효과적으로 차폐할 수 있고, 유연물질의 발생을 최소화하여 유효성분의 안정성을 확보할 수 있다. The pharmaceutical composition of the present invention can effectively mask the bitter taste of solifenacin or a pharmaceutically acceptable salt thereof and secure the stability of active ingredients by minimizing generation of related substances.
또한, 본 발명의 약제학적 제제는 쓴맛을 차폐하여 연하력이 약한 고령 환자의 복약순응도를 크게 개선하면서 기존 제제와 비교하여 동등한 약리효과를 달성할 수 있다.In addition, the pharmaceutical preparation of the present invention can achieve equivalent pharmacological effects compared to existing preparations while greatly improving the medication compliance of elderly patients with weak swallowing ability by masking the bitter taste.
이하, 본 발명을 실시예 및 실험예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예 및 실험예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예 및 실험예에 국한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are intended to illustrate the present invention, and the scope of the present invention is not limited to these Examples and Experimental Examples.
실험예 1. 가소제 용량에 따른 용출 시험 및 쓴맛 차폐 효과 시험Experimental Example 1. Dissolution test and bitter taste masking effect test according to plasticizer capacity
가소제인 트리아세틴의 함량을 조절하여 하기 표 1과 같이 비교예 1, 비교예 2 및 실시예 1의 약제학적 제제를 제조하였다. 이에 따른 용출률 및 쓴맛 차폐 결과는 하기 표 2에 나타내었다.Pharmaceutical preparations of Comparative Example 1, Comparative Example 2 and Example 1 were prepared as shown in Table 1 below by adjusting the content of triacetin as a plasticizer. The dissolution rate and bitter taste masking results according to this are shown in Table 2 below.
[표 1][Table 1]
[표 2][Table 2]
* 용출 시험* Dissolution test
가) 용출시험조건A) Dissolution test conditions
(1) 용 출 법 : 대한민국약전 제 2 법(paddle 법) (1) Dissolution method: Korean Pharmacopoeia 2 method (paddle method)
(2) 용 출 액 : pH 1.2 시험액, pH 6.8 시험액, 900 mL (2) Elution solution: pH 1.2 test solution, pH 6.8 test solution, 900 mL
(3) 온 도 : 37 ± 0.5 ℃ (3) Temperature: 37 ± 0.5 ℃
(4) 회전속도 : 50 rpm (4) Rotation speed: 50 rpm
나) 기기작동조건b) Equipment operating conditions
(1) 검 출 기 : 자외부흡광광도계(측정파장 : 210 nm) (1) Detector: Ultraviolet absorbance photometer (measurement wavelength: 210 nm)
(2) 칼 럼 : Symmetry C18(3.9 mm × 150 mm, 5.0 μm) 또는 이와 동등한 칼럼 (2) Column: Symmetry C18 (3.9 mm × 150 mm, 5.0 μm) or an equivalent column
(3) 주 입 량 : 10 μL (3) Injection amount: 10 μL
(4) 유 량 : 1.0 mL/분 (4) Flow rate: 1.0 mL/min
(5) 칼럼온도 : 30℃ 부근의 일정 온도 (5) Column temperature: constant temperature around 30 ℃
(6) 검액온도 : 10℃ 부근의 일정 온도 (6) Sample solution temperature: constant temperature around 10℃
(7) 이 동 상 : 인산칼륨 완충액(pH 3.0)과 아세토니트릴의 혼합액(6 : 4) (7) Mobile phase: A mixture of potassium phosphate buffer (pH 3.0) and acetonitrile (6:4)
(인산칼륨 완충액 (pH 3.0) : 인산일수소칼륨 8.7 g을 정밀히 달아 1L 용량플라스크에 넣고 정제수로 완전히 녹인 후, 인산으로 pH 3.0 ± 0.05가 되도록 조정한 액) (Potassium phosphate buffer (pH 3.0): Precisely weigh 8.7 g of potassium monohydrogen phosphate into a 1L volumetric flask, completely dissolve in purified water, and then adjust the pH to 3.0 ± 0.05 with phosphoric acid)
* 고미 정도의 확인: 고미는 맛측정 기기를 이용하여 주성분의 유무에 따른 기준 설정 후 상대적인 값 변화로 고미정도를 분류하여 평가하였다 (Masking). 실제 맛 확인을 통해 고미 정도의 변화를 확인하여 맛측정 기기의 값과 비교 확인 평가를 추가로 수행하였다.* Confirmation of degree of bitterness: After setting standards according to the presence or absence of the main ingredient, bitterness was evaluated by classifying the degree of bitterness according to the relative value change using a taste measuring device (Masking). Through actual taste confirmation, the change in bitter taste was confirmed, and a comparison confirmation evaluation with the value of the taste measurement device was additionally performed.
위 표 2의 결과를 보면, 가소제의 도입량이 증가할수록 솔리페나신 또는 이의 약제학적으로 허용가능한 염의 초기 용출율이 감소하면서 고미 정도도 감소하고, 실시예 1에서는 고미가 거의 느껴지지 않음을 확인하였다. 이는 구강 내에서 솔리페나신의 초반 용출을 억제하여 쓴맛을 차폐하고 위장관에서는 솔리페나신의 용출을 원활히 하여 동등한 약리 효과를 얻은 것으로 파악된다.Looking at the results of Table 2 above, it was confirmed that as the introduction amount of the plasticizer increased, the initial dissolution rate of solifenacin or a pharmaceutically acceptable salt thereof decreased and the degree of bitter taste also decreased, and in Example 1, bitter taste was hardly felt. It is understood that the same pharmacological effect was obtained by suppressing the initial dissolution of solifenacin in the oral cavity to mask the bitter taste and facilitating the dissolution of solifenacin in the gastrointestinal tract.
실험예 2. 가소제 종류에 따른 용출시험 및 쓴맛 차폐 효과 시험Experimental Example 2. Dissolution test and bitter taste shielding effect test according to plasticizer type
실시예 1의 가소제를 프로필렌글리콜(PG) 또는 폴리에틸렌글리콜(PEG)로 변경하여 하기 표 3과 같이 약제학적 제제를 제조하였다. 이에 따른 용출률 및 쓴맛 차폐 결과는 하기 표 4에 나타내었다(측정방법은 실험예 1과 동일함).A pharmaceutical formulation was prepared as shown in Table 3 below by changing the plasticizer of Example 1 to propylene glycol (PG) or polyethylene glycol (PEG). The dissolution rate and bitter taste masking results according to this are shown in Table 4 below (the measurement method is the same as in Experimental Example 1).
[표 3][Table 3]
[표 4][Table 4]
위 표 4의 결과를 보면, 가소제를 프로필렌글리콜(PG) 또는 폴리에틸렌글리콜(PEG)을 사용한 경우에도 실시예 1과 마찬가지로 솔리페나신 또는 이의 약제학적으로 허용가능한 염의 초기 용출율이 감소하면서 고미가 거의 느껴지지 않음을 확인하였다.Looking at the results of Table 4 above, even when propylene glycol (PG) or polyethylene glycol (PEG) was used as the plasticizer, the initial dissolution rate of solifenacin or a pharmaceutically acceptable salt thereof decreased as in Example 1, and the taste was almost felt. Confirmed not supported.
실험예 3. MUPS 펠렛의 도입 비율에 따른 쓴맛 차폐 효과 시험Experimental Example 3. Bitter taste shielding effect test according to the introduction ratio of MUPS pellets
실시예 1의 경우 MUPS 펠렛 도입 비율이 36.5 중량%이다. 하기 표 5와 같이 MUPS 펠렛의 도입 비율을 각각 50%로 증가시킨 약제학적 제제(비교예 3)를 제조하였다. 실시예 1과 비교예 3의 쓴맛 차폐 결과는 하기 표 6에 나타내었다.In the case of Example 1, the MUPS pellet introduction ratio is 36.5% by weight. As shown in Table 5 below, a pharmaceutical preparation (Comparative Example 3) was prepared in which the introduction ratio of MUPS pellets was increased to 50%, respectively. The bitter taste masking results of Example 1 and Comparative Example 3 are shown in Table 6 below.
[표 5][Table 5]
[표 6][Table 6]
위 표 6에 나타난 바와 같이, MUPS 펠렛의 도입 비율을 증가할수록 펠렛 손상이 증가하여 쓴맛 차폐 효과가 감소하여 고미가 발생하였음을 확인할 수 있다. 따라서, MUPS 펠렛의 도입 비율이 40 중량% 이하일 때 고미에 대한 맛 차폐 가능함을 알 수 있다.As shown in Table 6 above, it can be confirmed that as the introduction ratio of MUPS pellets increases, the damage to the pellets increases and the bitterness shielding effect decreases, resulting in bitterness. Therefore, it can be seen that when the introduction ratio of MUPS pellets is 40% by weight or less, it is possible to mask the bitter taste.
실험예 4. 유기용매에 따른 안정성 평가Experimental Example 4. Stability evaluation according to organic solvent
항산화제의 가용화를 위해 코팅액 제조 시 유기용매를 사용한 약제학적 제제(비교예 4)를 하기 표 7과 같이 제조하였다. 이에 대한 안정성 평가 결과는 하기 표 8에 나타내었다.A pharmaceutical formulation (Comparative Example 4) using an organic solvent when preparing a coating solution for solubilization of an antioxidant was prepared as shown in Table 7 below. The stability evaluation results for this are shown in Table 8 below.
[표 7][Table 7]
[표 8][Table 8]
* 유연물질 실험방법* Test method for related substances
가) 보관조건 : 40 ± 2.0 ℃A) Storage condition: 40 ± 2.0 ℃
나) 기기작동조건b) Equipment operating conditions
(1) 검 출 기 : 자외부흡광광도계(측정파장 : 220 nm) (1) Detector: Ultraviolet absorbance photometer (measurement wavelength: 220 nm)
(2) 칼 럼 : Capcell Pak C18(4.6 mm × 150 mm, 5.0 μm) 또는 이와 동등한 칼럼 (2) Column: Capcell Pak C18 (4.6 mm × 150 mm, 5.0 μm) or an equivalent column
(3) 주 입 량 : 10 μL (3) Injection amount: 10 μL
(4) 유 량 : 1.0 mL/분 (4) Flow rate: 1.0 mL/min
(5) 칼럼온도 : 40℃ 부근의 일정 온도 (5) Column temperature: constant temperature around 40 ℃
(6) 검액온도 : 4℃ 부근의 일정 온도 (6) Sample solution temperature: constant temperature around 4℃
(7) 이 동 상 : (7) Lee Bronze Award:
A - pH 7.5 완충액과 메탄올의 혼합액(9 : 1)을 인산으로 pH 7.5가 되도록 조정한 액 A - A mixture of pH 7.5 buffer and methanol (9:1) adjusted to pH 7.5 with phosphoric acid
B - pH 7.5 완충액주3)과 메탄올의 혼합액(1 : 9)을 인산으로 pH 7.5가 되도록 조정한 액 B - A mixture of pH 7.5 buffer Note 3) and methanol (1:9) adjusted to pH 7.5 with phosphoric acid
pH 7.5 완충액: 인산수소캄륨(K2HPO4) 3.4 g과 트리플루오로아세트산(TFA) 1 mL를 취하여 1 L 용량플라스크에 넣고 정제수로 녹인 후 트리에틸아민(TEA)으로 pH 7.5 ± 0.05가 되도록 조정한 액pH 7.5 buffer solution: Take 3.4 g of potassium hydrogen phosphate (K 2 HPO 4 ) and 1 mL of trifluoroacetic acid (TFA), put them in a 1 L volumetric flask, dissolve them in purified water, and adjust the pH to 7.5 ± 0.05 with triethylamine (TEA). adjusted amount
(8) 분석시간 : 70분 (8) Analysis time: 70 minutes
위 표 8에 나타난 바와 같이 가속 조건의 6개월 안정성 시험 결과, 약물층 용액의 용매로 에탄올을 첨가한 비교예 4에서 실시예 1보다 유연물질이 더 높게 나타남을 확인할 수 있다. 따라서, 약물층 용액의 용매로 유기용매(Ethanol, Acetone 등)를 사용할 경우 코팅 과정 중 정전기 발생으로 인해 코팅 효율이 급격히 낮아지며, MUPS 펠렛의 안정성도 감소함을 알 수 있다.As shown in Table 8 above, as a result of the 6-month stability test under accelerated conditions, it can be confirmed that related substances appear higher than in Example 1 in Comparative Example 4 in which ethanol was added as a solvent for the drug layer solution. Therefore, it can be seen that when using an organic solvent (Ethanol, Acetone, etc.) as a solvent for the drug layer solution, the coating efficiency is rapidly lowered due to the generation of static electricity during the coating process, and the stability of the MUPS pellets is also reduced.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not limiting. The scope of the present invention should be construed as including all changes or modifications derived from the meaning and scope of the claims to be described later and equivalent concepts rather than the detailed description above are included in the scope of the present invention.
Claims (12)
상기 코어층은 백당, 만니톨, 소르비톨, 유당, 감자전분, 옥수수전분, 히드록시에틸셀룰로오스, 미결정셀룰로오스, 백납, 카르나우바 왁스, 미결정 왁스 및 이들의 혼합물로 이루어진 군에서 선택되며,
상기 약물층(2)은 솔리페나신 또는 이의 약제학적으로 허용가능한 염 및 가소제를 함유하는 약제학적 제제로서,
상기 가소제는 트리아세틴이고,
상기 가소제는 약물층(2) 총 중량 기준 7 중량% 이상이고,
상기 약제학적 제제는 다중 유닛 펠렛 시스템으로 설계되고,
상기 다중 유닛 펠렛이 제제의 총 중량 기준 0 초과 40 중량% 이하인 약제학적 제제. It includes a core layer (1) and a drug layer (2) coated on the core layer (1),
The core layer is selected from the group consisting of white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethyl cellulose, microcrystalline cellulose, white wax, carnauba wax, microcrystalline wax, and mixtures thereof,
The drug layer 2 is a pharmaceutical preparation containing solifenacin or a pharmaceutically acceptable salt thereof and a plasticizer,
The plasticizer is triacetin,
The plasticizer is 7% by weight or more based on the total weight of the drug layer (2),
The pharmaceutical formulation is designed as a multi-unit pellet system,
A pharmaceutical formulation wherein the multi-unit pellets are greater than 0 and less than or equal to 40% by weight based on the total weight of the formulation.
상기 코어층은 백당, 만니톨, 소르비톨, 유당, 감자전분, 옥수수전분, 히드록시에틸셀룰로오스, 미결정셀룰로오스, 백납, 카르나우바 왁스, 미결정 왁스 및 이들의 혼합물로 이루어진 군에서 선택되며,
상기 약물층(2)은 솔리페나신 또는 이의 약제학적으로 허용가능한 염 및 가소제를 함유하는 약제학적 제제로서,
상기 가소제는 트리아세틴이고,
상기 가소제는 코어층(1) 및 약물층(2) 합산 중량 기준 3 중량% 이상이고,
상기 약제학적 제제는 다중 유닛 펠렛 시스템으로 설계되고,
상기 다중 유닛 펠렛이 제제의 총 중량 기준 0 초과 40 중량% 이하인 약제학적 제제. It includes a core layer (1) and a drug layer (2) coated on the core layer (1),
The core layer is selected from the group consisting of white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethyl cellulose, microcrystalline cellulose, white wax, carnauba wax, microcrystalline wax, and mixtures thereof,
The drug layer 2 is a pharmaceutical preparation containing solifenacin or a pharmaceutically acceptable salt thereof and a plasticizer,
The plasticizer is triacetin,
The plasticizer is 3% by weight or more based on the total weight of the core layer (1) and the drug layer (2),
The pharmaceutical formulation is designed as a multi-unit pellet system,
A pharmaceutical formulation wherein the multi-unit pellets are greater than 0 and less than or equal to 40% by weight based on the total weight of the formulation.
상기 코어층은 백당, 만니톨, 소르비톨, 유당, 감자전분, 옥수수전분, 히드록시에틸셀룰로오스, 미결정셀룰로오스, 백납, 카르나우바 왁스, 미결정 왁스 및 이들의 혼합물로 이루어진 군에서 선택되며,
상기 약물층(2)은 솔리페나신 또는 이의 약제학적으로 허용가능한 염 및 가소제를 함유하는 약제학적 제제로서,
상기 약물층(2) 위에 코팅 기제로 코팅되는 코팅층(3)을 더 포함하고,
상기 가소제는 트리아세틴이고,
상기 가소제는 코어층(1), 약물층(2) 및 코팅층(3) 합산 중량 기준 2.5 중량% 이상이고,
상기 약제학적 제제는 다중 유닛 펠렛 시스템으로 설계되고,
상기 다중 유닛 펠렛이 제제의 총 중량 기준 0 초과 40 중량% 이하인 약제학적 제제. It includes a core layer (1) and a drug layer (2) coated on the core layer (1),
The core layer is selected from the group consisting of white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethyl cellulose, microcrystalline cellulose, white wax, carnauba wax, microcrystalline wax, and mixtures thereof,
The drug layer 2 is a pharmaceutical preparation containing solifenacin or a pharmaceutically acceptable salt thereof and a plasticizer,
Further comprising a coating layer (3) coated with a coating base on the drug layer (2),
The plasticizer is triacetin,
The plasticizer is 2.5% by weight or more based on the total weight of the core layer (1), drug layer (2) and coating layer (3),
The pharmaceutical formulation is designed as a multi-unit pellet system,
A pharmaceutical formulation wherein the multi-unit pellets are greater than 0 and less than or equal to 40% by weight based on the total weight of the formulation.
(S-2) 코팅 기제를 함유하는 용액을 상기 약물층(2)에 분무하여 코팅하는 단계;
를 포함하는 제 1 항 내지 제 9 항 중 어느 하나의 항에 따른 약제학적 제제의 제조방법으로서,
상기 코어층은 백당, 만니톨, 소르비톨, 유당, 감자전분, 옥수수전분, 히드록시에틸셀룰로오스, 미결정셀룰로오스, 백납, 카르나우바 왁스, 미결정 왁스 및 이들의 혼합물로 이루어진 군에서 선택되며,
상기 가소제는 트리아세틴이고,
상기 가소제는 약물층(2) 총 중량 기준 7 중량% 이상이고,
상기 약제학적 제제는 다중 유닛 펠렛 시스템으로 설계되고,
상기 다중 유닛 펠렛이 제제의 총 중량 기준 0 초과 40 중량% 이하인 제조방법.(S-1) coating the core layer (1) by spraying a drug layer solution containing solifenacin or a pharmaceutically acceptable salt thereof and a plasticizer; and
(S-2) coating the drug layer 2 by spraying a solution containing a coating base;
A method for producing a pharmaceutical formulation according to any one of claims 1 to 9, comprising:
The core layer is selected from the group consisting of white sugar, mannitol, sorbitol, lactose, potato starch, corn starch, hydroxyethyl cellulose, microcrystalline cellulose, white wax, carnauba wax, microcrystalline wax, and mixtures thereof,
The plasticizer is triacetin,
The plasticizer is 7% by weight or more based on the total weight of the drug layer (2),
The pharmaceutical formulation is designed as a multi-unit pellet system,
The manufacturing method in which the multi-unit pellets are more than 0 and 40% by weight or less based on the total weight of the formulation.
The method of claim 11, wherein the solvent of the drug layer solution is water.
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| KR20210114271A (en) | 2021-09-23 |
| KR102628438B1 (en) | 2024-01-23 |
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