KR101064503B1 - Fast-acting regular solid dispersion comprising an extract of Salvia miltiorrhiza, the oral formulation comprising the same and the preparation method thereof - Google Patents
Fast-acting regular solid dispersion comprising an extract of Salvia miltiorrhiza, the oral formulation comprising the same and the preparation method thereof Download PDFInfo
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Abstract
본 발명은 단삼 추출물의 속효성 고체 분산체, 이를 함유한 경구용 제제 및 이들의 제조방법에 관한 것으로서, 상세하게는 본 발명은 단삼 추출물에 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 첨가한 후, 이를 용매에 함께 용해시킨 후, 이를 건조함으로서 수득한 고체 분산체에 약제학적으로 허용되는 부형제를 첨가하여 경구용 제제를 얻는 제조방법으로서, 이 제제는 기존의 단삼 추출물 함유 제제들보다 용해도 증가, 용출율 및 안정성이 대폭 향상된 단삼 추출물을 함유한 속효성 고체 분산체, 또한 이를 함유한 경구용 제제 및 이들의 제조방법에 관한 것이다. The present invention relates to a fast-acting solid dispersion of salvia extract, oral preparations containing the same, and a preparation method thereof. Specifically, the present invention relates to a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer of salvia extract. -polyoxypropylene-polyoxyethylene copolymer) is prepared by dissolving it in a solvent and then drying it to obtain an oral formulation by adding a pharmaceutically acceptable excipient to the solid dispersion obtained. The present invention relates to a fast-acting solid dispersion containing a salvia extract, which has significantly improved solubility, dissolution rate and stability compared to those containing soybean extract, and an oral preparation containing the same and a method for preparing the same.
단삼, 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체, 고체 분산체, 경구용 제제 Salvia Radix, Polyoxyethylene-Polyoxypropylene-Polyoxyethylene Copolymer, Solid Dispersion, Oral Formulations
Description
본 발명은 속효성 고체 분산체, 이를 함유한 경구용 제제 및 이들의 제조방법에 관한 것이다. The present invention relates to fast-acting solid dispersions, oral preparations containing the same, and methods for their preparation.
[문헌 1] M.S. Kislalioglu et al., Physical characterization and dissolution properties of ibuprofen: Eudragit coprecipitates, J. Pharm. Sci., 80, pp799-804, 1991MS 1 Kislalioglu et al., Physical characterization and dissolution properties of ibuprofen: Eudragit coprecipitates, J. Pharm. Sci., 80 , pp 799-804, 1991
[문헌 2] G. Van den Mooter et al., Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25, Eur. J. Pharm. Sci., 12, pp261-269, 2001G. Van den Mooter et al., Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25, Eur. J. Pharm. Sci ., 12 , pp 261-269, 2001
[문헌 3] S. Sethia and E. Squillante, Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods, Int. J. Pharm., 272, pp1-10, 2004S. Sethia and E. Squillante, Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods, Int. J. Pharm. , 272 , pp 1-10, 2004
[문헌 4] H. Hao et al., Pharmacokinetics, absorption and tissue distribution of tanshinone IIA solid dispersion, Plant. Med., 72(14), pp1311-1317, 2006H. Hao et al., Pharmacokinetics, absorption and tissue distribution of tanshinone IIA solid dispersion, Plant. Med ., 72 (14) , pp1311-1317, 2006
[문헌 5] W. Ling et al., Complexation of tanshinone IIA with 2-hydroxypropyl-β-cyclodextrin: Effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats, Int. J. Pharm., 341, pp58-67, 2007W. Ling et al., Complexation of tanshinone IIA with 2-hydroxypropyl-β-cyclodextrin: Effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats, I nt. J. Pharm. , 341 , pp58-67, 2007
[문헌 6] 특허등록 10-0830186호[Document 6] Patent Registration No. 10-0830186
[문헌 7] 특허등록 10-0827938호[Document 7] Patent Registration No. 10-0827938
단삼(Salvia miltiorrhiza)은 통화식물목 꿀풀과의 뿌리로부터 조제된 중요한 전통 약용식물로서, 그 활성 성분은 크립토탄시논(Cryptotanshinone), 탄시논 I(Tanshinone I), 탄시논 IIA(Tanshinone IIA) 등으로 알려져 있으며, 관상동맥 확장, 콜레스테롤 강하, 혈압 강하, 간기능 활성화, 진정 항염, 항암, 항균 작용의 약리작용을 갖는다고 알려져 있다.Salvia miltiorrhiza is an important traditional medicinal plant prepared from the roots of the moss family of the moss-tree. Its active ingredients are Cryptotanshinone, Tanshinone I, and Tanshinone IIA. It is known to have a pharmacological effect of coronary artery dilatation, cholesterol lowering, blood pressure lowering, liver function activation, soothing anti-inflammatory, anticancer, antibacterial action.
이러한 단삼의 건조된 뿌리는 혈액순환의 개선과 울혈의 치료를 위해 전통적으로 사용되어왔다. 또한 단삼은 관상동맥 질환과 고지혈증 그리고 뇌혈관 질환과 같은 증상의 예방에도 널리 이용된다. 현재 정제, 캡슐제 과립제, 주사제, 경구액제등 다양한 형태의 단삼제형이 있다. 하지만 이와 같이 많은 종류의 단삼 제형이 유통되고 있지만, 단삼 주요성분의 낮은 수용성과 용출률로 인하여 생체 이용률이 낮다. 또한 몇몇 성분들은 빛과 온도, 습도에 민감하게 영향을 받기 때문에 함량의 편차가 커지게 되며, 이는 투약시 약효에 영향을 미친다.Dried roots of these ginsengs have been traditionally used to improve blood circulation and treat congestion. Salvia is also widely used for the prevention of symptoms such as coronary artery disease, hyperlipidemia and cerebrovascular disease. Currently, there are various forms of sweet ginseng, such as tablets, capsule granules, injections, oral solutions. However, although many types of salvia formulations are in circulation, bioavailability is low due to low water solubility and dissolution rate of the main components of salvia. In addition, some components are sensitive to light, temperature, and humidity, and thus have a large variation in content, which affects drug efficacy during administration.
상기한 바와 같이, 일반적으로 물에 잘 녹지 않는 난용성 약물들의 용출율 및 생체 이용률을 증가시키기 위해 흔히 사용되었던 제제화 기술로는, 대개 미분화(micro-particulation), 계면활성제의 사용, 고체 분산체의 형성 등의 기술들이 시도되어 온 바 있으며, 특히 난용성 약물의 용해도 개선을 위한 연구의 일환으로 고체 분산체를 이용한 연구들이 많이 시도 되어 왔다 (M.S. Kislalioglu et al., Physical characterization and dissolution properties of ibuprofen: Eudragit coprecipitates, J. Pharm. Sci., 80, pp799-804, 1991; G. Van den Mooter et al., Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25, Eur. J. Pharm. Sci., 12, pp261-269, 2001).As mentioned above, formulation techniques commonly used to increase the dissolution rate and bioavailability of poorly soluble drugs, which are generally insoluble in water, usually include micro-particulation, the use of surfactants, and the formation of solid dispersions. And other techniques have been attempted, and many studies have been attempted using solid dispersions as part of studies to improve solubility of poorly soluble drugs (MS Kislalioglu et al., Physical characterization and dissolution properties of ibuprofen: Eudragit). coprecipitates, J. Pharm. Sci. , 80 , pp799-804, 1991; G. Van den Mooter et al., Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25, Eur. J. Pharm. Sci. , 12 , pp261 -269, 2001).
이러한 고체 분산체가 약물의 용해도를 증진시키는 기전은 담체간의 단순 공융 혼합물, 고용체, 글라스 솔루션(glass solution), 글라스 서스펜션(glass suspension), 결정 담체 속의 무정형 침전물, 혼합체나 복합체의 형성 등의 상호작용에 기인한다고 알려져 있고, 그 밖의 다른 요인으로는 습윤성의 증가나 확산층에서 담체에 의한 약물의 용해성 증가, 입자도 감소 등도 역시 용출율을 증가시키는데 기여한다고 알려진 바 있다(S. Sethia and E. Squillante, Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods, Int. J. Pharm., 272, pp1-10, 2004).The mechanism by which these solid dispersions enhance drug solubility is due to the interaction between simple eutectic mixtures, solid solutions, glass solutions, glass suspensions, amorphous precipitates in crystal carriers, and the formation of mixtures or complexes between carriers. Other factors, such as increased wettability, increased solubility of the drug by the carrier in the diffusion layer, and reduced particle size, are also known to contribute to an increase in dissolution rate (S. Sethia and E. Squillante, Solid dispersion). of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods, Int. J. Pharm., 272 , pp 1-10, 2004).
이러한 연구들로는, 분무건조법(spray drying method), 담체로서 불활성 수용성 고분자 물질을 이용하는 공침법, 및 사이클로덱스트린(cyclodextrin)을 이용한 포접복합체(inclusion complex)의 제조방법 등 다양한 방법들이 보고되었으나, 각각의 방법은 구체적인 제조방법에 따라 약물의 용해도가 증가하는 정도가 불규칙할 뿐만 아니라, 이러한 방법들을 이용하기에는 제조방법 및 상업적인 측면에 있어서 효율성이 낮아 문제가 많았다.These studies have reported various methods such as spray drying method, coprecipitation method using inert water-soluble polymer material as carrier, and preparation method of inclusion complex using cyclodextrin, but each method has been reported. According to the specific manufacturing method, the degree of solubility of the drug is not only irregularly increased, but there are many problems in using these methods because of low efficiency in the manufacturing method and commercial aspects.
또한, 천연물을 이용한 치료제 개발시 원료의 산지 및 품질 등의 문제로 균일한 치료효과 및 규격화를 기대하기 어렵다. 또한 천연물로부터 단일성분을 분리하는 과정에서 분리시 소요되는 기간이 길며, 획득율이 낮고 천연물이 가지는 잠재 적 독성 등의 요인들로 천연물 치료제 개발은 쉽지 않다. 이에 본 발명자들은 이러한 천연물 치료제 개발과정의 단점을 극복할 수 있는, 균일한 치료효과와 규격화가 가능한 천연물의 표준화시료 제조 및 산업화가 가능하도록 절차가 간단하고 신속하며 저렴한 제조공정을 연구하여 그 제조방법을 특허출원하였다(대한민국 특허등록 10-0830186호 및 특허등록 10-0827938호).In addition, when developing a therapeutic using natural products, it is difficult to expect a uniform therapeutic effect and standardization due to problems such as production and quality of raw materials. In addition, in the process of separating a single component from natural products, it takes a long time to separate, and it is not easy to develop a natural product treatment due to factors such as low acquisition rate and potential toxicity of natural products. Therefore, the present inventors have studied the manufacturing process by simple, quick and inexpensive manufacturing process to enable the standardized sample production and industrialization of the natural product capable of uniform treatment effect and standardization, which can overcome the disadvantages of the development process of natural product therapeutics. Patent application (Korea Patent Registration No. 10-0830186 and Patent Registration No. 10-0827938).
그런데 아직 단삼 추출물에 관련해서는 경구 투여 시 체내로 흡수되는 과정에서 소화액에서의 용해도와 용출속도가 낮아 약물 흡수가 지연되어 생체이용률이 낮은 단점을 보완하기 위한, 약물의 가용화 또는 용출 속도의 증가를 목적으로 한 연구는 미흡한 실정이다.However, in relation to salvia extract, the solubility and dissolution rate in digestive fluids are lowered in the process of being absorbed into the body during oral administration, and the drug absorption is delayed to compensate for the low bioavailability. There is not enough research.
Hao 등은 단삼의 주요 구성성분 중 하나인 탄시논 IIA(tanshinone IIA)의 약동학적 연구 결과 낮은 용해성으로 인하여 혈중농도가 매우 낮게 나타났으며 이를 개선하기 위하여 제제학적 노력이 필요함을 기술하였으나 구체적인 방법을 제시하지는 못하였다(H. Hao et al., Pharmacokinetics, absorption and tissue distribution of tanshinone IIA solid dispersion, Plant. Med., 72(14), pp1311-1317, 2006). 단삼 추출물의 중요 구성성분인 탄시논 IIA(tanshinone IIA)의 용해도 개선을 위하여 히드록시프로필베타시클로덱스트린(hydroxypropyl-β-cyclodextrin)과 복합체를 형성하여 용해도를 크게 증진시켰으나 탄시논 IIA(tanshinone IIA)의 용해도보다 약 20배 가량의 히드록시프로필베타시클로덱스트린(hydroxypropyl-β-cyclodextrin)을 사용해야 하며 용해도 증진효과가 크지 못하였다(W. Ling et al., Complexation of tanshinone IIA with 2-hydroxypropyl-β -cyclodextrin: Effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats, Int. J. Pharm., 341, pp58-67, 2007). Ji 등은 살비아놀릭 산(salvianolic acid)와 탄시논(tanshionone)을 함유하는 마이크로에멀젼(microemulsion)을 제조하였으나 정제나 캅셀제에 비하여 사용상 불편한 점이 많다.Hao et al. Described the pharmacokinetic studies of tanshinone IIA, one of the major constituents of salvia, indicating that blood concentrations were very low due to low solubility and that pharmaceutical efforts were needed to improve it. (H. Hao et al., Pharmacokinetics, absorption and tissue distribution of tanshinone IIA solid dispersion, Plant. Med ., 72 (14) , pp1311-1317, 2006). In order to improve the solubility of tanshinone IIA, which is an important component of salviae extract, complexation with hydroxypropyl-β-cyclodextrin enhanced the solubility, but it did not improve the solubility of tanshinone IIA. About 20 times the solubility of hydroxypropyl beta cyclodextrin (hydroxypropyl-β-cyclodextrin) should be used and solubility enhancement effect was not significant (W. Ling et al., Complexation of tanshinone IIA with 2-hydroxypropyl-β -cyclodextrin : Effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats, Int. J. Pharm. , 341 , pp58-67, 2007). Ji et al prepared a microemulsion containing salvianolic acid and tanshionone, but it is inconvenient to use compared to tablets or capsules.
따라서, 본 발명자들은 상기 문제점들을 해결하기 위하여 단삼 추출물의 용해도, 용출율 및 안정성을 개선하여 생체 이용률을 향상시키는 속효성 경구용 제제를 제조하기 위한 연구에 매진한 바, 단삼 추출물에 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 첨가한 후, 이를 용매에 함께 용해시킨 후, 이를 건조함으로서 수득한 고체 분산체에 약제학적으로 허용되는 부형제를 첨가하여 경구용 제제를 얻는 제조방법을 개발하여 본 발명을 완성하였다.Accordingly, the present inventors have been focused on the preparation of fast-acting oral preparations to improve the bioavailability by improving the solubility, dissolution rate and stability of salvia extract in order to solve the above problems, polyoxyethylene-polyoxy After adding a propylene-polyoxyethylene-polyoxyethylene copolymer, dissolving it in a solvent, and then drying it, a pharmaceutically acceptable excipient is added to the solid dispersion obtained to prepare an oral preparation. The production method was obtained to complete the present invention.
상기 목적을 달성하기 위해, 본 발명은 단삼 추출물 및 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 함유한 속효성 고체 분산체를 제공한다.In order to achieve the above object, the present invention provides a fast-acting solid dispersion containing a salvia extract and a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer.
또한, 본 발명은 단삼 추출물에 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 첨가한 후, 이를 용매에 함께 용해시키는 제 1단계; 이를 건조시키는 제 2단계 를 포함하는 공정을 통하여 수득되는 고체 분산체의 제조방법을 제공한다.In addition, the present invention is the first step of adding a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) to the extract of Salvia, then dissolving it in a solvent; It provides a method for producing a solid dispersion obtained through a process comprising a second step of drying it.
또한, 추가적으로 본 발명은 단삼 추출물에 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 첨가한 후, 이를 용융시키는 제 1단계; 이를 실온에서 냉각시키는 제 2단계를 포함하는 공정을 통하여 수득되는 고체 분산체의 제조방법을 제공한다.In addition, the present invention is the first step of adding a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) to the extract, and then melting it; It provides a method for producing a solid dispersion obtained through a process comprising a second step of cooling it at room temperature.
본원에서 정의되는 “단삼 추출물”은 크립토탄시논(Cryptotanshinone), 탄시논 I(Tanshinone I), 탄시논 IIA(Tanshinone IIA) 등의 지표성분을 다량, 바람직하게는 40 ~ 90 중량% 함유하는 단삼추출물을 포함한다. “Ginseng extract” as defined herein is a salvia containing a large amount, preferably 40 to 90% by weight of indicator components such as Cryptotanshinone, Tanshinone I, and Tanshinone IIA. Contains extracts.
또한, 본원에서 정의되는 “단삼 추출물”은 수용성 성분 및 지용성 성분을 모두 포함하며, 바람직하게는 지용성 성분을 함유하는 것을 특징으로 하는 단삼 추출물을 포함한다.In addition, the term “salty extract” as defined herein includes both a water-soluble component and a fat-soluble component, and preferably includes a salvia extract, which is characterized by containing a fat-soluble component.
본원에서 정의되는 “단삼 추출물”은 물, 메탄올, 에탄올, 부탄올 등의 탄소수 1 내지 4의 저급알코올 또는 이들의 혼합용매로부터 선택된 용매, 바람직하게는 물 및 에탄올 혼합용매, 보다 바람직하게는 50~100% 에탄올에 가용한 단삼 추출물을 포함한다.As defined herein, the "soybean extract" is a solvent selected from lower alcohols having 1 to 4 carbon atoms such as water, methanol, ethanol, butanol, or a mixed solvent thereof, preferably a mixed solvent of water and ethanol, more preferably 50-100 Contains salvia extracts available in% ethanol.
본원에서 정의되는 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)는 폴록사머(Poloxamer)라는 이름으로 널리 사용되고 있으며 HO(C2H4O)a(C3H6O)b(C2H4O)aH의 일반식으로 표시된다. 미국약전에 제시되어 있는 일반적으로 사용되는 다양한 폴록사 머로서, 바람직하게는 폴록사머 188®, 237®, 338® 또는 407®, 보다 바람직하게는 폴록사머 407®을 포함한다. Polyoxyethylene-polyoxypropylene-polyoxyethylene copolymers as defined herein are widely used under the name of poloxamer and HO (C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) is represented by the general formula of a H. Various commonly used poloxamers as set forth in the US Pharmacopeia, preferably poloxamer 188 ® , 237 ® , 338 ® or 407 ® , more preferably poloxamer 407 ® .
상기 본 발명에 사용된 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)는 비이온성 계면활성제로서 친수성을 나타내며 단삼 추출물 주위환경을 친수성화 시킴으로서 용해도를 증가시키며, 약물을 용해시키는데 필요한 활성화 에너지를 최소화시키는 역할을 할 뿐만 아니라, 상기 단삼 추출물의 용해도 및 용출율을 극대화 시키고, 생체막투과율을 증진시킴과 동시에 물리적 또는 화학적인 안정성을 유지하는 역할을 한다.The polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer used in the present invention exhibits hydrophilicity as a nonionic surfactant and increases solubility by hydrophilizing the surrounding environment of Salvia extract, and drug. Not only plays a role of minimizing the activation energy required to dissolve, but also maximizes the solubility and dissolution rate of the extract, and improves the biomembrane permeability and at the same time serves to maintain physical or chemical stability.
상기 활성 성분인 단삼추출물 건조 중량에 대하여 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)는 상대적인 중량 배합비가 1: 0.2∼20 중량비, 바람직하게는 1: 2∼15중량비, 보다 바람직하게는 1: 4∼10 중량비로 배합됨이 바람직하며, 상세하게는 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)는 전체 고체 분산체 조성물 중량의 약 17 내지 95 중량%, 바람직하게는 67 내지 94 중량%, 보다 바람직하게는 80 내지 91 중량%을 포함됨이 바람직하다.The relative weight blending ratio of polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer with respect to the dry weight of the salvia extract, which is the active ingredient, is 1: 0.2-20 weight ratio, preferably 1: 2- It is preferable to mix | blend 15 weight ratio, More preferably, it is 1: 4-10 weight ratio, Specifically, the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer is the whole solid dispersion composition It is preferred that about 17 to 95% by weight, preferably 67 to 94% by weight, more preferably 80 to 91% by weight.
상기 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)의 함량이 17 중 량% 미만에서는 고체 분산체 조성물 내에서 무정형 약물보다 결정형 약물의 비율이 높아지기 때문에 높은 용해도를 기대하기 어려우며, 95 중량% 초과에서는 더 이상의 용해도 향상 효과를 기대하기 어려우며, 또한 고체 분산체 조성물 전체 용량이 증가함으로서 환자가 복용하기에는 부담이 되기 때문에 환자의 순응도를 떨어뜨릴 수가 있어 바람직하지 않다.If the content of the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) is less than 17% by weight, the solubility of the crystalline drug is higher than that of the amorphous drug in the solid dispersion composition. It is difficult to expect, and more than 95% by weight, it is difficult to expect any further solubility improvement effect, and also increase the total dose of the solid dispersion composition, which is a burden for the patient to take, which is not preferable because it can reduce the patient's compliance.
상기한 고체 분산체를 제조하는 제 1단계의 용해는 당업계에 통상적인 용융법(melting method) 또는 용매법 (solvent method)을 사용할 수 있으며, 예를 들어, 상기 생약 추출물과 같은 시료 약물과 담체를 적절한 무게비로 분산용매에 녹인 후(함께 또는 따로 녹여 하나로 혼합한다), 고체 분산체를 얻기 위하여 분산용매를 휘발시켜 제거하는 방법이고, 분산 용매는 수계 용매(물을 포함하는 혼합용매)나 유기용매(메탄올, 에탄올, 아세톤 등 휘발성이 높은 유기용매)를 사용할 수 있으나, 이들에 한정되는 것은 아니다. Dissolution of the first step of preparing the solid dispersion may use a melting method or a solvent method conventional in the art, for example, a sample drug and a carrier, such as the herbal extract. Is dissolved in a dispersion solvent in an appropriate weight ratio (together together or separately and mixed together), and then a volatilization solvent is removed to obtain a solid dispersion. The dispersion solvent is an aqueous solvent (mixed solvent containing water) or organic solvent. A solvent (an organic solvent having high volatility such as methanol, ethanol, acetone, etc.) may be used, but is not limited thereto.
본원에서 정의되는 용매로는 단삼 추출물 및 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 동시에 용해시킬 수 있는 약제학적으로 허용되는 용매는 모두 사용가능하며, 그 예로는 디클로로메탄, 클로로포름, 에탄올, 메탄올, 아세톤, 이소프로탄올, 프로판올 등을 단독으로 또는 2종 이상을 혼합한 용매를 들 수 있으며, 본 발명은 상기 예시된 용매에만 한정하지는 않는다.As the solvent defined herein, any of the pharmaceutically acceptable solvents capable of simultaneously dissolving the salvia extract and the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer can be used. Examples include a solvent in which dichloromethane, chloroform, ethanol, methanol, acetone, isoprotanol, propanol and the like are used alone or in combination of two or more thereof. The present invention is not limited to the solvents exemplified above.
상기 단삼 추출물은 통상적인 추출방법에 의해 수득된 단삼 추출물을 사용할 수 있으며, 그 외에 건조한 단삼 중량의 약 1 내지 1000배, 바람직하게는 약 10 내지 100배 부피량(w/v%)의 정제수를 포함한 물, 메탄올, 에탄올, 부탄올 등의 탄소수 1 내지 4의 저급알코올 또는 이들의 혼합용매로부터 선택된 용매에, 1 내지 24 시간, 바람직하게는 2 내지 12 시간 동안, 10 내지 100℃, 바람직하게는 30 내지 80℃에서, 냉침추출, 열수추출, 초음파 추출, 환류냉각 추출, 또는 가열추출법 등의 추출방법으로, 바람직하게는 환류냉각 추출법으로 추출한 후 여과하고 감압 농축 및 건조과정을 통하여 조추출물을 얻는 제 1단계: 상기 조추출물 중량의 1 내지 10배, 바람직하게는 3 내지 6배 부피의 물을 넣어 현탁시켜 여과하여 수불용성 잔사를 얻는 제 2단계; 상기 잔사에 정제수를 포함한 물, 메탄올, 에탄올, 부탄올 등의 탄소수 1 내지 4의 저급알코올 또는 이들의 혼합용매로부터 선택된 용매, 바람직하게는 물 및 에탄올 혼합용매, 보다 바람직하게는 50 ~ 100% 에탄올을 가하여, 교반, 용해 및 여과과정을 통하여 여액을 얻는 제 3단계; 상기 여액의 잔류 용매를 제거하는 단계를 포함함을 특징으로 하는 본 발명의 단삼 추출물을 얻을 수 있다. The Dansam extract can be used for extracting the salvia extract obtained by a conventional extraction method, in addition to about 1 to 1000 times, preferably about 10 to 100 times the volume (w / v%) of purified water of dry salvia 10 to 100 ° C., preferably 30 to 1 to 24 hours, preferably 2 to 12 hours, in a solvent selected from a lower alcohol having 1 to 4 carbon atoms or a mixed solvent thereof such as water, methanol, ethanol, butanol, and the like. At 80 ° C., an extraction method such as cold sediment extraction, hot water extraction, ultrasonic extraction, reflux cooling extraction, or heat extraction method, preferably extracting by reflux cooling extraction, filtering, and obtaining crude extract through concentration under reduced pressure and drying. Step 1: a second step of suspending by adding 1 to 10 times the weight of the crude extract, preferably 3 to 6 times the volume of water suspension and filtered; A solvent selected from C1 to C4 lower alcohols such as water containing purified water, methanol, ethanol and butanol or a mixed solvent thereof, preferably a water and ethanol mixed solvent, more preferably 50 to 100% ethanol Adding, to obtain a filtrate through stirring, dissolution and filtration; Salvia extract of the present invention comprising the step of removing the residual solvent of the filtrate can be obtained.
상기 단삼 추출물의 추출방법은 본 출원인이 특허출원한 대한민국 특허등록 10-0827938호에 보다 상세히 기재되어 있다.The extracting method of the Dansam extract is described in more detail in Korean Patent Registration No. 10-0827938 to which the applicant has applied for a patent.
상기한 본 발명의 제조방법으로 제조된 단삼 추출물을 함유한 고체 분산체는 상기 단삼 추출물의 용해도 및 용출율을 극대화 시키고, 생체막 투과율을 증진시킴과 동시에 물리적 또는 화학적인 안정성을 유지하는 역할을 하여 본 발명의 단삼 추출물의 생체 흡수율을 향상시키는 효과를 갖는다.The solid dispersion containing the salvia extract prepared by the preparation method of the present invention as described above maximizes the solubility and dissolution rate of the salvia extract, enhances the membrane permeability and simultaneously maintains physical or chemical stability. It has the effect of improving the bioabsorption of Salvia extract.
또한 본 발명은 단삼 추출물과 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에 틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 함유한 고체 분산체 및 약제학적으로 허용되는 경구용 담체 또는 부형제를 함유한 속효성 경구용 제제를 제공한다.In addition, the present invention is a fast-acting agent containing a solid dispersion containing a salvia extract and a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer and a pharmaceutically acceptable oral carrier or excipient. Oral formulations are provided.
또한, 본 발명은 단삼 추출물에 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 첨가한 후, 이를 용매에 함께 용해시키는 제 1단계; 이를 건조함으로서 고체 분산체를 수득하는 제 2단계; 이 분산체에 약제학적으로 허용되는 경구용 담체 또는 부형제를 첨가하는 단계를 포함하는 단삼 추출물을 함유한 속효성 경구용 제제를 얻는 제조방법을 제공한다.In addition, the present invention is the first step of adding a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) to the extract of Salvia, then dissolving it in a solvent; Drying it to obtain a solid dispersion; It provides a preparation method for obtaining a fast-acting oral preparation containing a salvia extract, comprising the step of adding a pharmaceutically acceptable oral carrier or excipient to the dispersion.
추가적으로, 본 발명은 단삼 추출물에 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 첨가한 후, 이를 용융시키는 제 1단계; 이를 실온에서 냉각함으로서 고체 분산체를 수득하는 제 2단계; 이 분산체에 약제학적으로 허용되는 경구용 담체 또는 부형제를 첨가하는 단계를 포함하는 단삼 추출물을 함유한 속효성 경구용 제제를 얻는 제조방법을 제공한다. In addition, the present invention comprises the first step of adding a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) to the extract, and then melting it; A second step of obtaining a solid dispersion by cooling it at room temperature; It provides a preparation method for obtaining a fast-acting oral preparation containing a salvia extract, comprising the step of adding a pharmaceutically acceptable oral carrier or excipient to the dispersion.
본원에서 정의되는 경구용 담체 또는 부형제로는 아비셀(Avicel), 산셀(Sancel) 등의 미세 결정성 셀룰로오스; 제제가 산화되는 것을 방지하는 비타민 C 등의 항산화제; 지방산 또는 지방산 알코올 등의 첨가제; 백당, 맥아이온 엿, 정백당, 젤라틴, 설탕 및 물엿과 같은 당류; 스테아린산 마그네슘, 탈크, 콜로이드성 실리콘디옥사이드와 같은 활택제; 인산 일수소 칼슘, 전분, 만니톨과 같은 부형제; 소디움 스타치 글리콜레이트(Sodium starch glycolate), 크로스포비돈 (cross povidone), 저치환 하이드록시프로필 셀룰로오스(HPC), 칼슘 카르복시메틸셀룰로오스(CMC) 등의 붕해제; 및 필요에 따라, 착향제, 방부제, 방향제, 감미료, 색소, pH조절제 및 점도 조절제를 추가로 포함할 수 있으며, 이들은 단삼 추출물에 대하여 통상으로 사용되는 통상의 사용량을 첨가하는 것이 바람직하다.Oral carriers or excipients as defined herein include microcrystalline celluloses such as Avicel, Sancel, etc .; Antioxidants such as vitamin C to prevent the preparation from oxidizing; Additives such as fatty acids or fatty alcohols; Sugars such as white sugar, macion syrup, white sugar, gelatin, sugar and starch syrup; Lubricants such as magnesium stearate, talc, colloidal silicon dioxide; Excipients such as calcium monohydrogen phosphate, starch, mannitol; Disintegrants such as sodium starch glycolate, cross povidone, low-substituted hydroxypropyl cellulose (HPC), calcium carboxymethyl cellulose (CMC); And, if necessary, flavoring agents, preservatives, fragrances, sweeteners, pigments, pH adjusting agents and viscosity adjusting agents may be further included, and these are preferably added to the usual usage amount commonly used for salvia extract.
본 발명의 조성물에 사용될 수 있는 지방산 또는 지방산 알코올로는 구연산, 올레인산, 스테아릴 알코올, 미리스틱산, 리놀렌산 또는 라우릭산, 카프릭산, 카프릴릭산, 카프로익산 등이 사용될 수 있으나, 이들에 한정되는 것은 아니다.Citric acid, oleic acid, stearyl alcohol, myristic acid, linolenic acid or lauric acid, capric acid, caprylic acid, caproic acid, etc. may be used as the fatty acid or fatty alcohol that may be used in the composition of the present invention, but is not limited thereto. It doesn't happen.
본 발명의 조성물에 사용될 수 있는 항산화제는 부틸화된 히드록시톨루엔(butylated hydroxytoluene), 소듐 바이설파이트(sodium bisulfite), α-토코페놀(α-tocopherol), 비타민 C (ascorbic acid), β-카로틴(β-carotin), 토코페놀 아세테이트(tocopherol acetate), 푸마릭산(fumaric acid), 날릭산(nalic acid), 부틸화된 히드록시아니솔(butylated hydroxyanisole), 프로필 갈레이트(propyl galate) 및 소듐 아스코베이트(sodium ascorbate) 등이 사용될 수 있으나, 가장 바람직하게는, 비타민 C (ascorbic acid)이나 이에 한정되는 것은 아니다.Antioxidants that can be used in the compositions of the present invention are butylated hydroxytoluene, sodium bisulfite, α-tocopherol, vitamin C (ascorbic acid), β- Β-carotin, tocopherol acetate, fumaric acid, nalic acid, butylated hydroxyanisole, propyl galate and sodium Ascorbate may be used, but most preferably, but is not limited to vitamin C (ascorbic acid).
본 발명의 조성물에 사용될 수 있는 착향제는 혼합과일향, 사과향, 딸기향, 포도향, 체리향, 박하향, 바닐라향, 요구르트향, 드링크향 등이 사용될 수 있으나, 이들에 한정되는 것은 아니다.Flavoring agents that can be used in the composition of the present invention may be mixed fruit flavor, apple flavor, strawberry flavor, grape flavor, cherry flavor, peppermint flavor, vanilla flavor, yogurt flavor, drink flavor and the like, but are not limited thereto.
본 발명의 조성물에 사용될 수 있는 방부제는 안식향산, 안식향산나트륨, 에틸파라벤, 메틸파라벤, 프로필파라벤 등이 사용될 수 있으나, 이들에 한정되는 것 은 아니다.Preservatives that can be used in the composition of the present invention may be used, but are not limited to benzoic acid, sodium benzoate, ethyl paraben, methyl paraben, propyl paraben and the like.
본 발명의 조성물에 사용될 수 있는 방향제는 박하뇌, 박하유, 오렌지오일, 정향오일, 시나몬오일, 딸기에센스 및 기타 통상의 과일향 및 식물의 에센스 등이 사용될 수 있으나, 이들에 한정되는 것은 아니다.Perfume that can be used in the composition of the present invention may be used, but is not limited to peppermint brain, peppermint oil, orange oil, clove oil, cinnamon oil, strawberry essence and other common fruit flavor and plant essence.
본 발명의 조성물에 사용될 수 있는 감미제는 정백당, 포도당, 과당 , 아스파탐, 스테비오사이드, 솔비톨, 만니톨, 올리고당, 물엿, 맥아이온 엿 등이 사용될 수 있으나, 이들에 한정되는 것은 아니다.Sweeteners that may be used in the compositions of the present invention may be used, but are not limited to, white sugar, glucose, fructose, aspartame, stevioside, sorbitol, mannitol, oligosaccharide, syrup, macion syrup, and the like.
본 발명의 조성물에 사용될 수 있는 색소는 녹색 3호, 적색 2호, 적색 3호, 청색 1호, 청색 2호, 황색 4호, 황색 5호, 수용성 만니톨, 캐러멜, 산화 티타늄, 산화 제이철 등이 사용될 수 있으나, 이들에 한정되는 것은 아니다.The pigments that can be used in the composition of the present invention are green No. 3, red No. 2, red No. 3, blue No. 1, blue No. 2, yellow No. 4, yellow No. 5, water-soluble mannitol, caramel, titanium oxide, ferric oxide, etc. Can be used, but is not limited to these.
본 발명의 조성물에 사용될 수 있는 pH 조절제는 탄산나트륨, 수산화나트륨, 수산화칼륨, 트리에탄올아민, 모노에탄올아민 등이 사용될 수 있으나, 이들에 한정되는 것은 아니다.PH adjusting agent that can be used in the composition of the present invention may be used, but is not limited to sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine, monoethanolamine and the like.
본 발명의 조성물에 사용될 수 있는 점도 조절제는 아카시아(acacia), 벤토나이트(bentonite), 알긴산(alginic acid), 프로필렌글리콜알지네이트(propylene glycol alginate), 폴리비닐피롤리돈(polyvinylpyrrolidone), 폴리비닐알코올(polyvinylalcohol), 카보폴(carbopol), 폴리카르보필(polycarbopil), 트라가칸트검(tragacanth gum), 잔탄검(xanthan gum) 등이 사용될 수 있으나, 이들에 한정되는 것은 아니다.Viscosity modifiers that can be used in the compositions of the present invention are acacia, bentonite, alginic acid, propylene glycol alginate, polyvinylpyrrolidone, polyvinylalcohol ), Carbopol, polycarbopil, tragacanth gum, xanthan gum, and the like may be used, but are not limited thereto.
보다 상세하게는, 한편 본 발명은 단삼 추출물 및 폴리옥시에틸렌-폴리옥시 프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 적당한 용매에 함께 용해시킨 후, 이를 건조하여 본 발명의 고체 분산체를 제조하고 이를 당업계에 잘 알려진 약제학적으로 허용 가능한 경구용 담체 또는 부형제로 제제화 함을 특징으로 하는 단삼 추출물의 속효성 경구용 제제의 제조방법을 제공한다.More specifically, on the other hand, the present invention is the soybean extract and polyoxyethylene-polyoxy propylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) is dissolved together in a suitable solvent, it is dried to disperse the solid of the present invention It provides a method for the preparation of fast-acting oral preparations of Salvia soybean extract, characterized in that the sieve is prepared and formulated into a pharmaceutically acceptable oral carrier or excipient well known in the art.
또한, 추가적으로, 보다 상세하게는, 본 발명은 단삼 추출물 및 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 혼합하여 용융시킨 후, 이를 실온에서 냉각하여 본 발명의 고체 분산체를 제조하고 이를 당업계에 잘 알려진 약제학적으로 허용 가능한 경구용 담체 또는 부형제로 제제화 함을 특징으로 하는 단삼 추출물의 속효성 경구용 제제의 제조방법을 제공한다.In addition, more specifically, the present invention is a mixture of the Dansam extract and polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) is mixed and melted, it is cooled at room temperature to the present invention It provides a method for the preparation of fast-acting oral preparations of Salvia Militiorrhiza extract, comprising preparing a solid dispersion of and formulating it into a pharmaceutically acceptable oral carrier or excipient well known in the art.
상기 제조공정에서 건조물의 유동성 향상을 목적으로 적당한 부형제를 첨가한 후 분산시킨 뒤에 건조할 수 있다. In the manufacturing process, an appropriate excipient may be added and dispersed for the purpose of improving the fluidity of the dried product, followed by drying.
또한 본원에서 정의되는 “경구용 제제”는 상기 단삼 추출물 함유 고체 분산체를 당업계에 통상적인 약제학적 방법에 의해 제조 가능한 정제, 환제, 제피 정제, 경질 캡슐제, 연질 캡슐제, 현탁제, 현탁 시럽제, 건조시럽제 등으로 제형화한 제제를 포함하는 것으로서, 단삼 추출물을 전체 조성물 대비하여 약 0.5 내지 50 중량%, 바람직하게는 2 내지 30 중량% 함유함을 특징으로 한다.In addition, the “oral formulation” as defined herein refers to tablets, pills, epidermal tablets, hard capsules, soft capsules, suspensions, suspensions, which can produce the solid dispersion containing Salvia extract by conventional pharmaceutical methods in the art. It includes a formulation formulated with a syrup, a dry syrup, etc., characterized in that it contains about 0.5 to 50% by weight, preferably 2 to 30% by weight relative to the total composition.
본 발명의 경구용 제제는 단삼 추출물을 함유한 고체 분산체를 이용하여 종래의 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)가 함유되지 않은 통상의 단삼 추출물 함유 제제보다 증가된 용해도, 및 용출율 그리고 제제의 개선된 안정성 등의 유리한 장점을 갖는다. The oral preparation of the present invention contains a conventional salvia extract which does not contain a conventional polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer using a solid dispersion containing a salvia extract. It has advantageous advantages such as increased solubility, dissolution rate, and improved stability of the formulation over the formulation.
상기에서 설명한 바와 같이, 본 발명의 단삼 추출물 및 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 함유한 고체 분산체를 포함하는 본 발명의 속효성 경구용 제제는 종래의 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)가 함유되지 않은 통상의 단삼 추출물 함유 제제보다 증가된 용해도, 및 용출율 그리고 제제의 개선된 안정성 등의 유리한 장점을 나타내므로 단삼 추출물을 함유한 속효성 경구용 제제 및 이의 제조방법으로 유용하게 이용할 수 있다 .As described above, the fast-acting oral preparation of the present invention comprising a solid dispersion containing the salvia extract of the present invention and a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer Advantageous advantages such as increased solubility, dissolution rate and improved stability of the formulation compared to conventional salvia extract containing no conventional polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer Therefore, it can be usefully used as a fast-acting oral preparation containing the extract of Dansam and its preparation method.
이하, 본 발명을 하기 실시예, 비교예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by the following Examples, Comparative Examples and Experimental Examples.
단, 하기 실시예, 비교예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 의해 한정되는 것은 아니다.However, the following Examples, Comparative Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.
실시예 1. 단삼 추출물 함유 고체 분산체(1)의 제조Example 1 Preparation of Solid Dispersion (1)
대한민국 특허등록 10-0827938호에 기술한 방법에 따라, 건조한 단삼 600g을 경동시장에서 구입하여 동일량의 증류수를 가한 후 12시간 실온에서 방치하여 수분을 흡수시키고 여기에 에탄올 5L를 가하여 2시간 동안 가열 환류 추출하고, 진공 여과하여 여액을 얻은 후, 감압 농축(EYELA사, N-1000, 일본)하여 단삼 조추출물 110g을 수득하였다. 상기 단삼 조추출물 110g에 증류수 400ml를 가하고 진탕 교반하여 균질하게 현탁시킨 후 여과하여 증류수에 불용부분인 잔사를 얻었다. 얻어진 잔사에 에탄올 1L를 가하여 교반하여 용해시킨 다음 여과하여 여액을 얻은 다음, 여액을 감압농축하여 에탄올 용매를 제거한 고형물 8.69g(수득률 : 원료 단삼으로부터 1.45%), 본 발명의 단삼 추출물(이하, “NS"라 명명함)을 수득하였다. 이 단삼 추출물 150mg 및 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)로서 폴록사머 407(루트롤 F127, BASF, 독일) 750mg을 각각 50ml의 메탄올에 완전히 녹인 후, 이 두 용액을 섞어 실온에서 감압하여 12시간 동안 건조하여 고체 분산체(이하, “S"라 명명함)를 수득하였다. According to the method described in Korean Patent Registration No. 10-0827938, 600 g of dried sweet ginseng was purchased at Gyeongdong Market, added with the same amount of distilled water, and left to stand at room temperature for 12 hours to absorb moisture, and 5L of ethanol was added thereto and heated for 2 hours. The mixture was extracted under reflux, vacuum filtered to obtain a filtrate, and then concentrated under reduced pressure (EYELA, N-1000, Japan) to obtain 110 g of crude ginseng extract. 400 ml of distilled water was added to 110 g of the crude ginseng extract, and the mixture was shaken and homogeneously suspended, and then filtered to obtain a residue as an insoluble portion in distilled water. 1 L of ethanol was added to the obtained residue, followed by stirring to dissolve the filtrate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 8.69 g of a solid obtained by removing the ethanol solvent (yield: 1.45% from raw soybean), the extract of the present invention (hereinafter, “ NS ”) 150 mg of this Salvia extract and 750 mg of Poloxamer 407 (Rutrol F127, BASF, Germany) as a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer After each of them was completely dissolved in 50 ml of methanol, the two solutions were mixed and dried under reduced pressure at room temperature for 12 hours to obtain a solid dispersion (hereinafter referred to as "S").
실시예 2. 단삼 추출물 함유 경구용 제제(1)의 제조Example 2. Preparation of oral preparation (1) containing Salvia extract
실시예 1의 방법으로 제조한 고체 분산체 48g과 아비셀101(FMC, 미국) 252g을 혼합하여, 로터리식 타정기(PP11D, Chamunda, India)로 타정하여 정제(이하, “S-M"라 명명함)를 제조하였다.48 g of the solid dispersion prepared by the method of Example 1 and 252 g of Avicel 101 (FMC, USA) were mixed and tableted with a rotary tablet press (PP11D, Chamunda, India) to give a tablet (hereinafter referred to as "SM"). Prepared.
실시예 3. 단삼 추출물 함유 고체 분산체의 제조(2)Example 3. Preparation of Salmon Extract-Containing Solid Dispersion (2)
본 발명의 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체에 의한 효과를 친수성 고분자로 알려진 폴리비닐피롤리돈의 첨가와 비교하기 위하여, 750mg의 폴리비닐피롤리돈(Kollidone K30, BASF, 독일)을 사용한 것을 제외하고는 상기 실시예 1과 동일한 방법, 및 동일한 조건으로 실시하여 단삼 추출물 함유 고체 분산체 (2)(이하, “S-P"라 명명함)를 제조하였다.In order to compare the effect by the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer of the present invention with the addition of polyvinylpyrrolidone known as a hydrophilic polymer, 750 mg of polyvinylpyrrolidone (Kollidone K30, BASF, Germany A solid dispersion (2) (hereinafter, referred to as “SP”) was prepared in the same manner as in Example 1 and under the same conditions except for using).
실시예 4. 단삼 추출물 함유 고체 분산체의 제조(3)Example 4. Preparation of Salmon Extract-Containing Solid Dispersion (3)
본 발명의 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체에 의한 효과를 포접화합물을 형성하는 것으로 알려진 히드록시프로필베타시클로덱스트린의 첨가와 비교하기 위하여, 750mg의 히드록시프로필베타시클로덱스트린 (hydroxypropyl-β-cyclodextrin)(Sigma Chem. Co.)을 사용한 것을 제외하고는 상기 실시예 1과 동일한 방법, 및 동일한 조건으로 실시하여 단삼 추출물을 함유한 시클로덱스트린 복합체(이하, “S-H"라 명명함)를 제조하였다.In order to compare the effect of the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer of the present invention with the addition of hydroxypropylbetacyclodextrin known to form clathrate compounds, 750 mg of hydroxypropylbetacyclodextrin (hydroxypropyl Cyclodextrin complex containing Salviae Radix extract, which was carried out in the same manner as in Example 1 and under the same conditions, except that -β-cyclodextrin) (Sigma Chem. Co.) was used (hereinafter, referred to as "SH"). Was prepared.
실시예 5. 단삼 추출물 함유 고체 분산체의 제조(4) Example 5 Preparation of Salmon Extract-Containing Solid Dispersion (4)
본 발명의 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체에 의한 효과를 친수성 고분자로 알려진 폴리에틸렌 글리콜의 첨가와 비교하기 위하여, 750mg의 폴리에틸렌 글리콜 8000(Sigma Chem. Co.)을 사용한 것을 제외하고는 상기 실시예 1과 동일한 방법, 및 동일한 조건으로 실시하여 단삼 추출물 함유 고체 분산체 (4)(이하, “S-E80"라 명명함)를 제조하였다.In order to compare the effect of the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer of the present invention with the addition of polyethylene glycol known as a hydrophilic polymer, 750 mg of polyethylene glycol 8000 (Sigma Chem. Co.) was used. Was carried out in the same manner as in Example 1, and under the same conditions to prepare a solid dispersion (4) (hereinafter referred to as "S-E80") containing the extract of Salvia.
실시예 6. 단삼 추출물 함유 고체 분산체의 제조(5)Example 6 Preparation of Salmon Extract-Containing Solid Dispersion (5)
본 발명의 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체에 의한 효과를 친수성 고분자로 알려진 폴리에틸렌 글리콜의 첨가와 비교하기 위하여, 750mg의 폴리에틸렌 글리콜 3400(Sigma 초드. Co.)을 사용한 것을 제외하고는 상기 실시예 1과 동일한 방법, 및 동일한 조건으로 실시하여 단삼 추출물 함유 고체 분산체 (5)(이하, “S-E34"라 명명함)를 제조하였다.In order to compare the effect of the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer of the present invention with the addition of polyethylene glycol known as a hydrophilic polymer, 750 mg of polyethylene glycol 3400 (Sigma Chod. Co.) was used. Was carried out in the same manner as in Example 1, and under the same conditions to prepare a solid dispersion (5) (hereinafter, referred to as "S-E34") containing the Salvia extract.
실시예 7. 단삼 추출물 함유 경구용 제제의 제조(2)Example 7 Preparation of Oral Formulation containing Salvia Extract (2)
실시예 3의 방법으로 제조한 고체 분산체 48g과 아비셀101(FMC, 미국) 252g을 혼합하여, 로터리식 타정기(PP11D, Chamunda, India)로 타정하여 정제(이하, “S-PM"이라 명명함)를 제조하였다.48 g of the solid dispersion prepared by the method of Example 3 and 252 g of Avicel 101 (FMC, USA) were mixed, tableted with a rotary tablet press (PP11D, Chamunda, India), hereinafter referred to as "S-PM". ) Was prepared.
비교예 1. 단삼 추출물 함유 3종의 단삼 시판 제제Comparative Example 1. Three types of commercially available salvia extract containing salvia extract
본 실험의 단삼 추출물의 속효성 고체 분산체, 이를 함유한 경구용 제제의 효능을 확인하기 위하여 중국에서 시판 중인 단삼 제제 3종을 사용하였다. 중국 Hebang사의 단삼 제제“He(이하, “시판품 1”이라 명명함), Baixingtang사의 단삼 제제 “Bai"(이하, “시판품 2”이라 명명함), Foci사의 단삼 제제 “Ci(이하, “ 시판품 3”이라 명명함)는 중국 시중에서 구입하였다.In order to confirm the efficacy of the fast-acting solid dispersion of the extract of the present experiment, oral preparations containing the same, three types of salvia extracts available in China were used. Hebang's salvia preparation "He" (hereinafter referred to as "commercial 1"), Baixingtang's salvia preparation "Bai" (hereinafter referred to as "commercial 2"), and Foci's saliva preparation "Ci (hereinafter,“ Commercial 3 ” Was purchased from China.
실험예 1. 용해도 비교실험Experimental Example 1. Solubility Comparative Experiment
실시예 1 및 실시예 3 내지 6의 방법으로 수득한 과량의 고체 분산체 분말 또는 단삼 추출물을 5㎖의 증류수에 넣고, 실온에서 750rpm으로 12시간 동안 마그네틱 바를 이용하여 교반한 후, 다시 12000rpm에서 10분간 원심분리하여 상등액을 취해서 메탄올로 적절히 희석한 후에 HPLC (LC-10, Shimadzu)에서 분석하였다. 고정상으로는 Gemini C18 (Phenomenex)을 사용하였으며 이동상은 물/아세토니트릴 (45/55)을 사용하였으며 검출은 자외부 270nm에서 실시하였다.Excess solid dispersion powder or Dansam extract obtained by the method of Example 1 and Examples 3 to 6 was put in 5 ml of distilled water, stirred at 750 rpm at room temperature for 12 hours using a magnetic bar, and then again at 10 000 rpm. The supernatant was removed by centrifugation for a minute, diluted appropriately with methanol, and analyzed by HPLC (LC-10, Shimadzu). Gemini C18 (Phenomenex) was used as the stationary phase, and water / acetonitrile (45/55) was used as the mobile phase, and detection was performed at 270 nm.
그 실험결과, 하기 표 1과 같이 상기 실시예 1, 실시예 3 내지 6의 방법으로 수득한 고체 분산체(S, S-P, S-H, S-E80, S-E34)와 실시예 1의 방법으로 수득한 순수한 단삼 추출물(NS)의 용해도를 비교해 보면, 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 이용한 단삼 추출물의 고체 분산체의 제조 시 용해도가 더 우수하였으며, 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)로서 폴록사머 407을 사용하여 제조한 고체 분산체(S)에서 용해도가 가장 크게 증가한 것을 확인할 수 있었다.As a result of the experiment, the solid dispersion (S, SP, SH, S-E80, S-E34) obtained by the method of Example 1, Examples 3 to 6, as shown in Table 1 obtained by the method of Example 1 When comparing the solubility of pure pure Salvia extract (NS), the solubility was better in preparing solid dispersion of Salvia extract using polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer. In the solid dispersion (S) prepared using poloxamer 407 as a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer, it was confirmed that the solubility increased the most.
실험예 2. 용출시험Experimental Example 2. Dissolution Test
상기 실시예 2 및 실시예 7의 방법으로 수득한 경구용 제제(S-M, S-PM)와 중국에서 시판 중인 3종의 단삼 제제(시판품 1, 2, 3)를 사용하여, 본원 발명이 용출 속도에 어떤 영향을 미치는지를 비교하기 위해, USP 용출시험 제 2법에 의해 pH 6.8의 완충용액 500㎖를 용출시험기(DST 810, Labfine, Inc., Suwon, Korea) vessel에 첨가하고 50rpm으로 교반하였다. 시간에 따라 용출액을 취할 때, 2㎖의 검액을 취하였고, 같은 양의 매질을 다시 넣어주었으며, 검액은 12000rpm에서 10분간 원심분리한 후, 메탄올로 희석하여 용해도 비교시험과 동일한 조건에서 HPLC로 분석하였다. Elution rate of the present invention using oral preparations (SM, S-PM) obtained by the method of Example 2 and Example 7 and three kinds of salviane preparations (commercially available products 1, 2, 3) in China To compare the effect, 500 ml of buffer solution pH 6.8 was added to the dissolution tester (DST 810, Labfine, Inc., Suwon, Korea) by the USP elution test method 2 and stirred at 50 rpm. When the eluate was taken over time, 2 ml of the sample solution was taken, and the same amount of medium was added again. The sample solution was centrifuged at 12000 rpm for 10 minutes, diluted with methanol, and analyzed by HPLC under the same conditions as the solubility comparison test. It was.
그 실험결과, 도 1-1 내지 1-3에서 볼 수 있는 바와 같이, 상기 실시예 2 및 실시예 7의 방법으로 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)를 사용하여 수득한 단삼 추출물의 고체 분산체를 이용하여 제조한 경구용 제제(S-M 및 S-PM)는 크립토탄시논(Cryptotanshinone)(도1-1), 탄시논 I(Tanshinone I)(도1-2), 탄시논 IIA(Tanshinone IIA)(도1-3)의 모든 성분에 있어서 중국 시판품 1, 2 및 3보다 용출율이 우수하였으며, 또한 폴리옥시에틸렌-폴리옥시프로필렌-폴리옥시에틸렌 공중합체 (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer)로서 폴록사머-407을 사용하여 단삼 추출물의 고체 분산체를 제조한 S-M 경구용 제제가 더 우수한 용출율를 나타냄을 확인할 수 있었다. As a result of the experiment, as shown in Figures 1-1 to 1-3, the polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer (polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer) by the method of Example 2 and Example 7 Oral preparations (SM and S-PM) prepared using solid dispersions of Salvia extracts obtained using) were obtained from Cryptotanshinone (Fig. 1-1) and Tanshinone I ( Fig. 1-2), the dissolution rate was better than that of Chinese commercial products 1, 2, and 3 in all components of Tanshinone IIA (Fig. 1-3), and polyoxyethylene-polyoxypropylene-polyoxyethylene air It was confirmed that the SM oral preparation prepared with the solid dispersion of Salvia Militiorrhiza extract using poloxamer-407 as a polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer showed better dissolution rate.
실험예 3. 안정성 시험Experimental Example 3. Stability Test
3개월 동안의 고체 분산체의 보관상 안정성 시험을 실시하였다. 세 가지 지표성분의 함량을 측정한 결과 상기 실시예 1 및 실시예 2의 방법으로 수득한 고체 분산체(S) 및 경구용 제제(S-M)에서 모두 함량 변화가 나타나지 않아, 안정성을 확인할 수 있었다.The storage stability test of the solid dispersion for 3 months was conducted. As a result of measuring the content of the three indicator components in the solid dispersion (S) and oral preparation (S-M) obtained by the method of Example 1 and Example 2 did not appear in the content change, it was confirmed the stability.
도 1-1은 상기 실시예 2 및 실시예 7의 방법으로 제조한 경구용 제제(S-M 및 S-PM)와 3종의 단삼 제제의 시판품(시판품 1, 2, 3)에 대한 크립토탄시논(Cryptotanshinone) 용출을 비교한 도이며,1-1 is a Cryptotansinone for commercial products (commercially available products 1, 2, and 3) of oral preparations (SM and S-PM) prepared by the methods of Examples 2 and 7 and three types of Salvia Militiorrhiza. (Cryptotanshinone) dissociation,
도 1-2은 상기 실시예 2 및 실시예 7의 방법으로 제조한 경구용 제제(S-M 및 S-PM)와 3종의 단삼 제제의 시판품(시판품 1, 2, 3)에 대한 탄시논 I(Tanshinone I) 용출을 비교한 도이며, 1-2 are tanshinone I (commercially available commercially available products (commercially available products 1, 2, 3) of the oral preparations (SM and S-PM) prepared by the method of Example 2 and Example 7) Tanshinone I) Comparison of elution,
도 1-3은 상기 실시예 2 및 실시예 7의 방법으로 제조한 경구용 제제(S-M 및 S-PM)와 3종의 단삼 제제의 시판품(시판품 1, 2, 3)에 대한 탄시논IIA(Tanshinone IIA) 용출을 비교한 도이다.1-3 are tanshinone IIA (commercially available products (commercially available products 1, 2, 3) of oral preparations (SM and S-PM) prepared by the method of Examples 2 and 7) and three types of Salvia Miltiorrhiza (commercially available products 1, 2, and 3); Tanshinone IIA) is a comparison of the elution.
Claims (12)
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| KR20100039033A KR20100039033A (en) | 2010-04-15 |
| KR101064503B1 true KR101064503B1 (en) | 2011-09-14 |
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| KR1020080098235A KR101064503B1 (en) | 2008-10-07 | 2008-10-07 | Fast-acting regular solid dispersion comprising an extract of Salvia miltiorrhiza, the oral formulation comprising the same and the preparation method thereof |
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| CN111407732A (en) * | 2020-03-03 | 2020-07-14 | 绍兴文理学院元培学院 | Preparation method and application of tanshinone IIA/sodium alginate solid dispersion |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070018900A (en) * | 2004-04-08 | 2007-02-14 | 와이어쓰 | Bazedoxifene acetate solid dispersion formulations |
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| KR20070018900A (en) * | 2004-04-08 | 2007-02-14 | 와이어쓰 | Bazedoxifene acetate solid dispersion formulations |
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