KR20230083444A - Ocular nanoemulsion composition for the treatment of macular degeneration - Google Patents
Ocular nanoemulsion composition for the treatment of macular degeneration Download PDFInfo
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- KR20230083444A KR20230083444A KR1020210171437A KR20210171437A KR20230083444A KR 20230083444 A KR20230083444 A KR 20230083444A KR 1020210171437 A KR1020210171437 A KR 1020210171437A KR 20210171437 A KR20210171437 A KR 20210171437A KR 20230083444 A KR20230083444 A KR 20230083444A
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- methyl
- methoxy
- phenyl
- dependent
- trimethoxychroman
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물로서, 기존 수난용성 약물의 물에 대한 용해도가 낮아 제제개발이 어렵고 제형으로부터의 용출률이 낮아 흡수가 불량해지는 문제를 적정 pH로 조절하여, 제제를 제조하면서 이를 극복했다. poorly water soluble drugs; an oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; a surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; And a pH-dependent nanoemulsion composition containing purified water, which is difficult to develop formulations due to the low solubility of existing poorly water-soluble drugs in water, and poor absorption due to low dissolution rate from the formulation. got over it
Description
본 발명은 황반변성 치료를 위한 안과용 나노이멀젼 조성물 및 이의 제조방법을 제공한다.The present invention provides an ophthalmic nanoemulsion composition for the treatment of macular degeneration and a method for preparing the same.
약물이 약효를 나타내기 위해서는, 약물이 투여부위로부터 혈중으로 흡수되고, 혈류를 따라서 작용을 나타내는 장기나 조직으로 이행하여야 한다. 따라서 적용부위 혹은 투여부위에서 흡수의 장벽으로 작용하는 피부나 위장관막, 또는 기타 비강점막, 질점막 등의 다양한 생체점막을 투과하여 혈중으로 이행될 수 있어야 하며, 따라서 각종 생체막을 통한 투과가 약물의 작용발현을 위해 필수적이다.In order for a drug to exhibit a medicinal effect, the drug must be absorbed into the blood from the site of administration and transferred to organs or tissues that exhibit an action along the bloodstream. Therefore, it must be able to pass through various biological mucous membranes such as the skin, gastrointestinal tract membrane, or other nasal mucosa and vaginal mucosa, which act as barriers to absorption at the site of application or administration, and pass into the blood. essential for action to occur.
그러나 약물들 중 생체막 투과 자체는 큰 어려움이 없으나, 물에 대한 용해도가 낮아 제제개발이 어렵고 제형으로부터의 용출률이 낮아 흡수가 불량해지는 경우가 빈번하다. 이러한 난용성 약물의 경우에는 가용화 전략이 필요한데, 가용화 방안으로 난용성 약물을 염이나 무정형 고체로 하거나 혹은 보조용매나 계면활성제를 첨가하는 전략들이 사용되고 있는바, 수난용성 약물의 가용성을 높이기 위해 계속해서 연구가 진행 중에 있는 실정이다. However, biomembrane permeation itself is not a big difficulty among drugs, but drug development is difficult due to low solubility in water, and absorption is often poor due to low dissolution rate from the dosage form. In the case of these poorly soluble drugs, a solubilization strategy is required. As a solubilization method, strategies to make poorly soluble drugs into salts or amorphous solids or to add co-solvents or surfactants are used. Research is currently in progress.
본 발명의 목적은 수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물을 제공하는 데에 있다.An object of the present invention is a poorly water-soluble drug; an oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; a surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; And to provide a pH-dependent nanoemulsion composition containing purified water.
본 발명의 또 다른 목적은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 치료용 약학 조성물 및 예방 또는 개선용 건강식품 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating macular degeneration and a health food composition for preventing or improving macular degeneration comprising the pH-dependent nanoemulsion composition.
본 발명의 또 다른 목적은 (a) 오일류 및 계면활성제를 중량비 1 : 1 내지 3로 혼합한 후, 55 내지 65 ℃에서 수난용성 약물을 첨가하여 용해시켜 유상을 제조하는 단계; (b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계; (c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및 (d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법을 제공하는 데에 있다.Another object of the present invention is (a) preparing an oil phase by mixing oils and surfactants in a weight ratio of 1: 1 to 3 and dissolving by adding a poorly water-soluble drug at 55 to 65 ° C; (b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative and water, and then adding a pH adjusting agent to adjust the pH to 4.5 to 6; (c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and (d) sterilizing the dispersed phase of step (c).
상기 목적을 달성하기 위하여, 본 발명은 수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물을 제공한다.In order to achieve the above object, the present invention is a poorly water-soluble drug; an oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; a surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; And it provides a pH-dependent nanoemulsion composition containing purified water.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating macular degeneration comprising the pH-dependent nanoemulsion composition.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or improving macular degeneration comprising the pH-dependent nanoemulsion composition.
또한, 본 발명은 (a) 오일류 및 계면활성제를 중량비 1 : 1 내지 3로 혼합한 후, 55 내지 65 ℃에서 수난용성 약물을 첨가하여 용해시켜 유상을 제조하는 단계; (b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계; (c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및 (d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법을 제공한다.In addition, the present invention (a) preparing an oil phase by mixing oils and surfactants in a weight ratio of 1: 1 to 3, and then adding and dissolving a poorly water-soluble drug at 55 to 65 ° C; (b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative and water, and then adding a pH adjusting agent to adjust the pH to 4.5 to 6; (c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and (d) sterilizing the dispersed phase of step (c).
본 발명은 수난용성 약물을 포함하는 pH 의존적 나노이멀젼 조성물에 관한 것으로, 수난용성 치료물질의 가용화, 안전하고 유효한 점안용 등의 첨가제로의 사용가능 및 물리화학적으로 안정화 효과가 있어, 무균여과로 대량생산이 가능한 제조방법으로 점안, 안구주사 및 경구제로 적용이 가능할 수 있다.The present invention relates to a pH-dependent nanoemulsion composition containing a poorly water-soluble drug, which can be used as an additive for solubilization of a poorly water-soluble therapeutic substance, safe and effective for eye drops, and has a physicochemical stabilizing effect. As a production method that can be produced, it can be applied to eye drops, intraocular injections, and oral preparations.
도 1은 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate; 이하, SH11037라고함)의 pH-stability 시험에서 얻어진 크로마토그램을 나타낸다.
도 2는 SH11037의 pH-stability에 따른 불순물 (Impurity) 생성 곡선과 대표적 조건의 크로마토그램을 나타낸다.
도 3은 나노 이멀젼 기제에 따른 60 ℃ (온수 중탕)에서의 용해도 (중량%) 평가를 나타낸다.
도 4는 MCT70과 계면활성제 및 피마자유와 계면활성제의 개별 중량비 혼합물의 물에 대한 분산시의 평균입자크기 평가를 나타낸다.
도 5는 나노이멀젼 기제 별 배합성 평가 결과를 나타낸다.
도 6은 SH11037의 최적화 점안제의 대표적 평가결과를 나타낸다.
도 7은 하기 실시예에 의해 제조된 1.5 중량% 점안제에 대한 가속조건 (40 ℃)에서의 간이 안정성 시험 결과를 나타낸다.
도 8은 다른 수난용성 물질인 1-(tert-부틸)3-(2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐)피페리딘-1,3-디카르복실레이트 (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate; 이하, SH-17040이라함), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페놀 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol; 이하, SH-17059라함), 5-((6-(사이클로프로필메톡시)-5,7-디메톡시크로만-3-일)메틸)-2-메톡시페놀 (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol; 이하, SH-19021이라함), 부틸((2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페녹시)카보닐)글리신 (butyl((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate; 이하, SHA-032라함), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(1-벤질피페리딘-4-일)카바메이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate; 이하, SHA-034라함) 및 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate; 이하, SH-17060이라함)에 대해, 하기 실시예에 의해 제조된 1.5 중량% 점안제와 동일한 첨가제 분량 및 제조방법에 따라서 제조하여 주요 품질항목에 대하여 평가한 결과를 나타낸다.1 shows 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate In the pH-stability test of (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate; hereinafter referred to as SH11037) The obtained chromatogram is shown.
Figure 2 shows the impurity (Impurity) production curve according to the pH-stability of SH11037 and the chromatogram of representative conditions.
Figure 3 shows the solubility (wt%) evaluation at 60 ℃ (hot water bath) according to the nano-emulsion base.
Figure 4 shows the average particle size evaluation of the dispersion in water of the mixture of MCT70 and surfactant and castor oil and surfactant in individual weight ratios.
5 shows the evaluation results of compoundability for each nanoemulsion base.
Figure 6 shows representative evaluation results of the optimized eye drop of SH11037.
Figure 7 shows the results of a simple stability test under accelerated conditions (40 ℃) for 1.5% by weight eye drops prepared by the following examples.
8 is another poorly water-soluble material, 1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl )piperidine-1,3-dicarboxylate (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl) phenyl)piperidine-1,3-dicarboxylate; hereinafter referred to as SH-17040), 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol (2- methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol; hereinafter referred to as SH-17059), 5-((6-(cyclopropylmethoxy)-5,7-dimethoxychloro Mann-3-yl)methyl)-2-methoxyphenol (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol; hereinafter referred to as SH-19021) , Butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl) methyl) phenoxy) carbonyl) glycine (butyl ((2-methoxy-5-(( 5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate; hereinafter referred to as SHA-032), 2-methoxy-5-((5,6,7-trimethoxychroman-3 -yl) methyl) phenyl (1-benzylpiperidin-4-yl) carbamate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl) methyl) phenyl (1-benzylpiperidin-4 -yl)carbamate; hereinafter referred to as SHA-034) and 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)- About L-phenylalaninate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate; hereinafter referred to as SH-17060) , It is prepared according to the same amount of additives and manufacturing method as the 1.5% by weight eye drop prepared in the following example, and the results of evaluation of the main quality items are shown.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
기존 수난용성 약물의 물에 대한 용해도가 낮아 제제개발이 어렵고 제형으로부터의 용출률이 낮아 흡수가 불량해지는 경우가 빈번한 문제를 해결하기 위해, 오일 및 계면활성제의 적절한 선택으로 인한 최적의 pH에서 가용화되고, 물질 안정성이 있는 본 발명을 완성했다.In order to solve the frequent problem of poor water absorption of existing poorly water-soluble drugs due to their low solubility in water, which makes it difficult to develop formulations and low dissolution rate from formulations, it is solubilized at the optimal pH due to the appropriate selection of oil and surfactant, We have completed the present invention with material stability.
본 발명은 수난용성 약물; MCT (Medium Chain Triglyceride) 또는 피마자유 (Castor Oil)에서 선택된 오일; 폴리옥실 35 캐스터 오일 (Polyoxyl 35 castor oil) 또는 폴리옥실 40 하이드로제네이티드 캐스터 오일 (Polyoxyl 40 hydrogenated castor oil)에서 선택된 계면활성제; 및 정제수를 포함하는 pH 의존적 나노이멀젼 조성물을 제공한다.The present invention is a poorly water-soluble drug; an oil selected from MCT (Medium Chain Triglyceride) or Castor Oil; a surfactant selected from Polyoxyl 35 castor oil or Polyoxyl 40 hydrogenated castor oil; And it provides a pH-dependent nanoemulsion composition containing purified water.
상기 조성물 총 100 중량%에 대하여 수난용성 약물을 바람직하게는 0.5 내지 2.0 중량%로 포함될 수 있으며, 더 바람직하게는 1.5 중량%일 수 있다.The poorly water-soluble drug may be preferably included in an amount of 0.5 to 2.0% by weight, more preferably 1.5% by weight, based on 100% by weight of the total composition.
상기 조성물은 오일 및 계면활성제를 1:(1~3)의 중량비율로 포함될 수 있다.The composition may include oil and surfactant in a weight ratio of 1:(1 to 3).
상기 pH는 바람직하게는 4.5 내지 6.5일 수 있으며, 더 바람직하게는 5 내지 6 일 수 있다. The pH may be preferably 4.5 to 6.5, more preferably 5 to 6.
상기 수난용성 약물은 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-부틸)3-(2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐)피페리딘-1,3-디카르복실레이트 (1-(tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페놀 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5-((6-(사이클로프로필메톡시)-5,7-디메톡시크로만-3-일)메틸)-2-메톡시페놀 (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol), 부틸((2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페녹시)카보닐)글리신 (butyl((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(1-벤질피페리딘-4-일)카바메이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(1-benzylpiperidin-4-yl)carbamate) 및 2-메톡시-5-((5,6,7-트리메톡시크로만-3-일)메틸)페닐(tert-부톡시카보닐)-L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate)로 이루어진 군에서 선택되는 하나일 수 있으나, 이에 한정 되는 것은 아니다.The poorly water-soluble drug is 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal Laninate (2-Methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylalaninate), 1-(tert-butyl)3- (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate (1-( tert-butyl)3-(2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl)piperidine-1,3-dicarboxylate), 2-methoxy-5 -((5,6,7-trimethoxychroman-3-yl)methyl)phenol (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenol), 5- ((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3-yl)methyl)-2-methoxyphenol (5-((6-(cyclopropylmethoxy)-5,7-dimethoxychroman-3 -yl)methyl)-2-methoxyphenol), butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycine (butyl ((2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenoxy)carbonyl)glycinate), 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl) Man-3-yl) methyl) phenyl (1-benzylpiperidin-4-yl) carbamate (2-methoxy-5-((5,6,7-trimethoxychroman-3-yl) methyl) phenyl (1- benzylpiperidin-4-yl)carbamate) and 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl(tert-butoxycarbonyl)-L-phenylal It may be one selected from the group consisting of 2-methoxy-5-((5,6,7-trimethoxychroman-3-yl)methyl)phenyl (tert-butoxycarbonyl)-L-phenylalaninate), but is limited thereto It is not.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating macular degeneration comprising the pH-dependent nanoemulsion composition.
상기 약학 조성물은 통상적인 방법에 따라 안구주사제, 점안제, 과립제, 산제, 정제, 환제, 캡슐제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다. The pharmaceutical composition may be any one formulation selected from the group consisting of eye injections, eye drops, granules, powders, tablets, pills, capsules, gels, suspensions, emulsions, drops or liquids according to conventional methods.
본 발명에 따른 유효성분의 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있고, 1일 투여량이 0.01 mg/kg 내지 200 mg/kg, 바람직하게는 0.1 mg/kg 내지 200 mg/kg, 보다 바람직하게는 0.1 mg/kg 내지 100 mg/kg 일 수 있다. 투여는 하루에 한번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다. The dosage of the active ingredient according to the present invention may vary depending on the condition and weight of the subject, the type and severity of the disease, the drug type, the route and duration of administration, and may be appropriately selected by a person skilled in the art, and the daily dosage is 0.01 mg. /kg to 200 mg/kg, preferably 0.1 mg/kg to 200 mg/kg, and more preferably 0.1 mg/kg to 100 mg/kg. Administration may be administered once a day or divided into several times, and the scope of the present invention is not limited thereby.
또한, 본 발명은 상기 pH 의존적 나노이멀젼 조성물을 포함하는 황반변성 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or improving macular degeneration comprising the pH-dependent nanoemulsion composition.
상기 건강기능식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다.The health functional food includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, It may contain organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like.
그밖에 천연 과일 주스, 합성 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 건강기능식품 조성물은 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알코올 및 비타민 복합제 중 어느 하나의 형태일 수 있다.In addition, it may contain fruit flesh for the production of natural fruit juice, synthetic fruit juice and vegetable beverages. These components may be used independently or in combination. In addition, the health functional food composition is any one form of meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin complex can be
또한, 상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합 여부는 다른 규정이 없는 한 식품의약품안전청에 승인된 식품첨가물공전의 총칙 및 일반 시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In addition, the health functional food may additionally contain food additives, and the suitability as a "food additive" is determined according to the general rules of the Food Additive Code and general test methods approved by the Korea Food and Drug Administration unless otherwise specified. It is judged according to the relevant standards and standards.
상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류 첨가 알칼리제, 보존료제제, 타르색소 제제 등의 혼합 제제류 등을 들 수 있다.Examples of items listed in the “Food Additives Codex” include, for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, goreng pigment, guar gum, L -Mixed preparations such as sodium glutamate preparations, noodle-added alkali preparations, preservative preparations, tar color preparations, and the like.
이때, 건강기능식품을 제조하는 과정에서 식품에 첨가되는 유효성분은 필요에 따라 그 함량을 적절히 가감할 수 있으며, 바람직하게는 식품 100 중량부에 1 중량부 내지 90 중량부 포함되도록 첨가될 수 있다.At this time, the content of the active ingredient added to the food in the process of manufacturing the health functional food may be appropriately increased or decreased as necessary, and preferably may be added so that 1 part by weight to 90 parts by weight is included in 100 parts by weight of the food. .
또한, 본 발명은 (a) 오일류 및 계면활성제를 중량비 1 : 1 내지 3로 혼합한 후, 55 내지 65 ℃에서 수난용성 약물을 첨가하여 용해시켜 유상을 제조하는 단계; (b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계; (c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및 (d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법을 제공한다.In addition, the present invention (a) preparing an oil phase by mixing oils and surfactants in a weight ratio of 1: 1 to 3, and then adding and dissolving a poorly water-soluble drug at 55 to 65 ° C; (b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative and water, and then adding a pH adjusting agent to adjust the pH to 4.5 to 6; (c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and (d) sterilizing the dispersed phase of step (c).
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 다만 하기의 시험예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예 등에 한정되는 것은 아니다. 본 발명의 실시예 등은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the following test examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. Examples of the present invention and the like are provided to more completely explain the present invention to those skilled in the art.
[실시예] 점안제 제조 방법[Example] Method for preparing eye drops
SH11037이 포함된 점안제제는 표 1의 원약분량표에 따라 하기와 같이, 제조했다.Eye drop formulations containing SH11037 were prepared as follows according to the original drug quantity table in Table 1.
(i) 오일 및 계면활성제 조합을 10 mL 바이알에 첨가 및 혼합한 후, 60 ℃ (물중탕)에서 주성분인 SH11037 5, 10 및 15 mg을 넣고, 마그네틱 바로 교반 하여 용해시켰다.(유상)(i) After adding and mixing the combination of oil and surfactant in a 10 mL vial, 5, 10, and 15 mg of SH11037, the main component, were added at 60 ° C (in water bath), and dissolved by stirring with a magnetic bar. (Oil phase)
(ii) 그 외에서 수산화나트륨 (NaOH)를 제외한 첨가제들은 표 1의 제제 분량에 맞게 각각 칭량하여 10 mL 바이알에 넣고, 증류수 10 mL를 넣어 충분히 교반 하여 용해시켰다. 그 후, 1N 수산화나트륨 (NaOH) 용액을 상기 (b) 단계의 용액에 적량 가하며 pH 6.0으로 조정했다.(수상)(ii) Other additives, except for sodium hydroxide (NaOH), were each weighed according to the amount of preparation in Table 1 and put into a 10 mL vial, and 10 mL of distilled water was added and sufficiently stirred to dissolve. Then, an appropriate amount of 1N sodium hydroxide (NaOH) solution was added to the solution in step (b) to adjust the pH to 6.0. (aqueous phase)
(iii) 약물의 손실를 줄이기 위해 상기 (i) 단계의 수상을 상기 (ii) 단계의 유상 바이알에 3 mL를 가하여 볼텍싱 1분하여 분산시키고, 이 분산상을 5 mL 용량플라스크에 옮겨 담았다.(iii) To reduce drug loss, 3 mL of the aqueous phase of step (i) was added to the oil phase vial of step (ii) and vortexed for 1 minute to disperse it, and the dispersed phase was transferred to a 5 mL volumetric flask.
(iv) 남은 상기 (i) 단계의 수상 1 mL로 상기 (ii) 단계의 유상 바이알의 잔류물을 세척하여 상기 (iii) 단계의 용량플라스크에 옮겨 담았고, 추가로 남은 수상 1 mL로 이 과정을 반복하여 유상 바이알에서 잔류하여 발생할 수 있는 손실을 최소화 했다.(iv) Wash the residue of the oil phase vial from step (ii) with 1 mL of the aqueous phase from step (i), transfer it to the volumetric flask from step (iii), and continue this process with 1 mL of the remaining aqueous phase. Repeatedly, losses that could occur due to remaining in the oil phase vial were minimized.
(v) 상기 (iv) 단계의 혼합액을 볼텍싱 1분을 하고, 남은 상기 (iii) 단계의 수상으로 5 mL 부피 플라스크를 표선했다.(v) The mixed solution of step (iv) was vortexed for 1 minute, and a 5 mL volumetric flask was filled with the remaining aqueous phase of step (iii).
(vi) 제균 여과를 위하여 클린벤치 (Clean bench)에서 0.22 μm Syringe filter로 여과 한 후, 멸균된 튜브에 담아 농도별 (0.5 중량%, 1.0 중량% 및 1.5 중량%)로 최종 점안제제 (이하, F18이라함)를 제조했다.(vi) After filtering with a 0.22 μm Syringe filter in a clean bench for sterilization filtration, put it in a sterilized tube and prepare final eye drops by concentration (0.5% by weight, 1.0% by weight and 1.5% by weight) (hereinafter, referred to as F18).
[시험예 1] 제형 및 기제 선정[Test Example 1] Formulation and base selection
1. SH11037의 pH-stability 평가1. Evaluation of pH-stability of SH11037
SH11037은 에스터 프로드러그 (ester prodrug)로 분류될 수 있으며, 도 1에 따를 때, 사전 안정성 연구에서 주요 분해생성물은 에스터 (ester) 결합 또는 아마이드 (amide) 결합이 절단되면서 생성되는 3-(3-하이드록시-4-메톡시벤질)-5,6,7-트리메톡시크로만-4-온 (3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one, SH11008; 이하, Impurity A라함) 및 2-메톡시-5-((5,6,7-트리메톡시-4-옥소크로만-3-일)메틸)페닐 L-페닐알라니네이트 (2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl L-phenylalaninate; 이하, Impurity B라함)임을 확인했다.SH11037 can be classified as an ester prodrug, and according to FIG. 1, the main degradation product in the preliminary stability study is 3-(3- Hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (3-(3-hydroxy-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one, SH11008; hereinafter referred to as Impurity A) and 2-methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl L-phenylalaninate (2- It was confirmed that methoxy-5-((5,6,7-trimethoxy-4-oxochroman-3-yl)methyl)phenyl L-phenylalaninate; hereinafter referred to as Impurity B).
점안제의 가장 중요한 특성 중에 하나인 pH에 따른 안정성을 평가하기 위하여 pH 2 내지 8까지의 수성완충액/에탄올 (부피비=6/4)를 사용하여 난용성 주성분을 40 ㎍/㎖의 농도로 녹이고, 40 ℃ 챔버에 보관하면서 일정시간 간격으로 샘플을 채취하여 HPLC 분석을 통해 분해생성물을 평가했다. 상기 수성완충액은 pH 2 내지 3 까지는 HCl/NaCl, pH 4 내지 5까지는 CH3COOH/CH3COONa, pH 6 내지 8 까지는 KH2PO4/Na2HPO4의 원료를 사용하였으며, 필요시 1N NaOH로 사용하여 정확히 원하는 pH로 조정하였다.In order to evaluate stability according to pH, which is one of the most important characteristics of eye drops, the poorly soluble active ingredient was dissolved at a concentration of 40 μg/ml using an aqueous buffer/ethanol (volume ratio = 6/4) of
그 결과, 도 2에 의할 때, pH-stability 시험에서 SH11037은 pH 5 내지 6의 범위에서 가장 안정함을 확인했다. 이는 점안제로서 비교적 낮은 pH 범위에 속하지만 안자극성을 감안하여도 설정 가능한 pH 범위였다. pH 4.0 이하이거나 pH 7.0 이상일 때 해당 수용액에서의 약물 분해가 급격히 증가하는 pH 의존적인 경향성을 분명히 나타내는 것을 확인했다. 도 1에서 Impurity A의 경우, 비교적 pH 7 이상의 조건에서 SH11037의 에스터 결합이 가수분해되면서 형성되고, 또한 이외의 경로로 Impurity B가 생성되더라도 이 역시 추가적인 에스터 결합 가수분해에 의해서 Impurity A로 전환되었다. Impurity B의 경우, 낮은 pH 조건에서의 주요생성물이며 SH11037의 아마이드 결합이 깨지면서 형성되었다. 기타 특별한 분해생성물은 관찰되지 않았고, 따라서 pH를 규명된 안정한 범위에서 설정하는 것이 점안제의 안정화에 크게 기여할 수 있을 것으로 판단했다.As a result, according to FIG. 2, it was confirmed that SH11037 was most stable in the range of
2. 용해도 평가2. Solubility Assessment
SH11037은 그 구조에서 벤젠고리 구조가 다수 포함되어 있어서 물에 대한 용해도가 불량하고, Log P가 4.82로서 지용성의 특성을 크게 나타낼 것으로 판단되었다. 수난용성이며 지용성을 나타내는 물질을 가용화하여 안전하고 유효한 제형으로는 나노이멀젼 제제가 있으며, 이미 점안제로 상용화된 사례가 있는데, 이러한 나노이멀젼 개발을 위해서는 우선적으로 점안으로 사용가능한 기제를 선정해야 했다. 따라서, 표 2과 같이, 국내에서 점안제로 사용가능한 나노이멀젼 기제를 식약처 및 FDA 데이터 베이스를 검색하여 선정하여 제제개발의 출발로 삼았다.SH11037 has poor solubility in water because it contains a large number of benzene ring structures in its structure, and its Log P is 4.82, which is considered to be highly lipid-soluble. There is a nanoemulsion formulation as a safe and effective formulation by solubilizing a substance that is poorly water-soluble and fat-soluble, and there is a case that has already been commercialized as an eye drop. Therefore, as shown in Table 2, the nanoemulsion base that can be used as an eye drop in Korea was searched and selected from the Ministry of Food and Drug Safety and FDA databases and used as a starting point for formulation development.
나노이멀젼 기제 중에는 실온에서 고체 또는 반고형의 상태를 나타내는 것들이 있어서 이들을 녹이고, 최대치의 가용성을 평가하기 위하여 60 ℃ 온수 중탕에서 용해도 평가를 실시했다. 적은 양의 SH11037 양을 고려한 용해도 평가 방법을 사용했는데, 각각의 기제 50 mg을 가온하고, SH11037을 3 mg씩 가하여 녹을 때까지 교반했다. 이 과정을 반복하여 충분히 교반하여도 녹지 않는 시점에 가해진 SH11037의 양을 산출하여 용해도를 계산했다. Among the nanoemulsion base materials, some of them were solid or semi-solid at room temperature, so they were dissolved, and solubility was evaluated in a warm water bath at 60 °C to evaluate the maximum solubility. A solubility evaluation method considering a small amount of SH11037 was used. 50 mg of each base was heated, and 3 mg of SH11037 was added and stirred until dissolved. By repeating this process, the solubility was calculated by calculating the amount of SH11037 added at the time when it was not dissolved even when sufficiently stirred.
그 결과, 도 3에 따를 때, 용해도 평가 결과에서 오일류에서는 O1, O2, O7에서 4 내지 9 중량%의 우수한 용해도를 나타내었으며, 계면활성제에서는 S2가 9 중량%를 나타냄으로 가장 높았고, 다른 계면활성제류도 의미 있는 용해도 값을 나타내는 것을 확인했다.As a result, according to FIG. 3, in the solubility evaluation results, oils showed excellent solubility of 4 to 9% by weight in O1, O2, and O7, and in surfactants, S2 was the highest with 9% by weight, and other surfactants It was confirmed that Ryu also showed a meaningful solubility value.
3. 나노이멀젼 구성 및 분산성 평가 (1)3. Nanoemulsion composition and dispersibility evaluation (1)
나노이멀젼을 구성하는 오일 및 계면활성제 조합을 선정하기 위하여 오일 및 계면활성제 24가지 조합을 배합하여 물에 대한 분산성 평가를 실시했다. 이 중, 상분리 없이 안정한 분산성을 나타내며, 200 nm 미만의 평균입자경을 나타내는 나노이멀젼을 나타내는 배합을 선정했다.In order to select oil and surfactant combinations constituting the nanoemulsion, 24 combinations of oil and surfactant were blended to evaluate dispersibility in water. Among these, formulations were selected that exhibited stable dispersibility without phase separation and nanoemulsion with an average particle diameter of less than 200 nm.
각각의 오일 및 계면활성제의 중량비를 1:3, 2:2 및 3:1의 비율로 변화시켜서 혼합하고, 이 혼합물 100 mg을 취하여 3 mL의 물에 분산시켜 성상을 관찰하고 입자크기를 측정하여 평가했다.Each oil and surfactant were mixed by changing the weight ratio of 1:3, 2:2, and 3:1, and 100 mg of this mixture was taken and dispersed in 3 mL of water to observe the properties and measure the particle size. Evaluated.
그 결과, 도 4에 따를 때, 총 24종의 평가 결과에서 MCT70 및 Cremophor EL 조합 내지는 Castor Oil 및 Cremophor EL 조합에서 100 nm 보다 작은 균질한 입자크기를 나타내며 안정한 나노이멀젼을 형성하는 것을 확인했다. 하지만, 기존 허가받은 점안제에 대한 사용 가능량에서 Castor Oil 및 Cremophor 조합이 MCT 및 Cremophor EL 조합보다 크기 때문에 가용화 능력 또한 클 것으로 예상되어, 나노이멀젼 제조를 위한 오일 및 계면활성제 조합으로 선정할 수 있었다.As a result, according to FIG. 4, in a total of 24 evaluation results, it was confirmed that the combination of MCT70 and Cremophor EL or the combination of Castor Oil and Cremophor EL showed a homogeneous particle size smaller than 100 nm and formed a stable nanoemulsion. However, since the combination of Castor Oil and Cremophor is greater than the combination of MCT and Cremophor EL in the usable amount of the existing approved eye drops, the solubilizing ability is also expected to be high, and the oil and surfactant combination for nanoemulsion preparation can be selected.
4. 나노이멀젼 구성 및 분산성 평가 (2)4. Nanoemulsion composition and dispersibility evaluation (2)
SH11037을 제외한 분산성 및 입자도 평가에서 선정된 오일 및 계면활성제의 조합에 대하여, SH11037을 가하여 60 ℃ (온수중탕)에서 가용화시켜 물을 사용해 분산시켜 침전유무를 평가하여 가용화 수준을 평가했다.For the combination of oil and surfactant selected in the dispersibility and particle size evaluation except for SH11037, SH11037 was added and solubilized at 60 ° C (hot water bath), and then dispersed using water to evaluate the presence or absence of precipitation to evaluate the solubilization level.
그 결과, 표 2에 따를 때, Cremophor EL에서 분산상 기준으로 SH11037을 1.5 중량%까지 가용화 가능하였으며, 분산상의 입자크기도 계면활성제가 70 중량% 이상에서 200 nm보다 작은 평균입자경을 나타내어서, 바람직한 나노이멀젼 구성의 오일 및 계면활성제 조합임을 확인했다.As a result, according to Table 2, it was possible to solubilize up to 1.5% by weight of SH11037 based on the dispersed phase in Cremophor EL, and the particle size of the dispersed phase also showed an average particle diameter smaller than 200 nm at 70% by weight or more of the surfactant, which is a desirable nanoe It was confirmed that it was a combination of oil and surfactant in the form of emulsion.
5. 나노이멀젼 구성 기제의 배합성 평가5. Evaluation of compoundability of nanoemulsion constituent base
12주 동안 40 ℃ 챔버에서 샘플을 보관하며 HPLC 분석을 통해 기제 및 약물간의 배합적합성 연구를 진행했다.Samples were stored in a chamber at 40 °C for 12 weeks, and mixing compatibility between the base and the drug was studied through HPLC analysis.
그 결과, 도 5에 따를 때, Cremophor 계열에서 약물의 분해율이 가장 크게 나타났고, TPGS에서 약물이 가장 안정한 것을 확인했다. 또한, 기제별로 약물의 분해율이 다른 요인을 분석하기 위해 샘플 각각의 pH를 측정한 결과, Cremophor 계열을 포함한 샘플의 pH가 7 이상이며, 약물의 분해율이 50 % 이상을 나타낸 것을 확인했다. 반면, 나머지 기제들은 pH 4 내지 6 사이의 범위에 들었고, 약물의 분해율이 4 내지 20 %의 범위를 나타내었다. 이를 통해, 각 기제의 pH 및 약물의 안정성간의 상관성이 매우 크다는 것을 재확인했다. As a result, according to FIG. 5, it was confirmed that the drug decomposition rate was the highest in the Cremophor series, and the drug was most stable in TPGS. In addition, as a result of measuring the pH of each sample to analyze the factors that differ in the drug dissolution rate for each agent, it was confirmed that the pH of the samples including Cremophor series was 7 or higher and the drug dissolution rate was 50% or higher. On the other hand, the rest of the bases were in the pH range of 4 to 6, and the drug dissolution rate was in the range of 4 to 20%. Through this, it was reconfirmed that the correlation between the pH of each base and the stability of the drug is very large.
6. 나노이멀젼 최적 제제 개발 및 점안제 평가결과6. Development of optimal formulation for nanoemulsion and evaluation results of eye drops
SH11037을 최대로 가용화하고, 분산상이 안정하면서 입자크기가 최소화된 점안제제를 개발하기 위하여 앞서 선정된 나노이멀젼 기제 및 추가로 pH 조절제, 삼투압제, 보존제를 사용하여 30여 가지의 처방을 제조 및 평가하여 상기 표 1의 원약분량표에 따른 SH11037 농도별 (0.5 중량%, 1.0 중량% 및 1.5 중량%) 점안제제 (F18) 후보를 도출했고, 상기 원약분량표 및 상기 실시예의 제조 방법에 따라서 제조된 점안제제에 대해서 중요한 품질특성에 대해서 평가했다. In order to develop an eye drop formulation with maximum solubility of SH11037, stable dispersion and minimized particle size, we prepared and evaluated about 30 prescriptions using the nanoemulsion base selected above and additionally a pH adjusting agent, an osmotic agent, and a preservative. Thus, candidates for eye drops (F18) were derived for each concentration of SH11037 (0.5% by weight, 1.0% by weight and 1.5% by weight) according to the original drug amount table in Table 1, and prepared according to the original drug amount table and the manufacturing method of the above example Eye drop formulations were evaluated for important quality characteristics.
그 결과, 도 6에 따를 때, 성상에서 균질하고 안정한 반투명의 콜로이드 나노입자 분산상을 나타내었으며, 주성분 농도가 감소함에 따라서 평균입자크기가 100 nm 부근에서 감소하는 경향을 나타내었다. 점안감과 직결되는 pH는 안정성 시험 결과를 바탕으로 pH 6으로 설정하였는데, 삼투성도 저장성으로 하여 제조하여 230 내지 250 mOsm의 범위를 나타냈다. pH 및 삼투성은 점안제제로서 사용가능한 수준이였다. 보존제 사용으로 인한 배합성 이슈도 없었으며, 무균화를 위한 멸균 여과도 가능하여 무균성의 달성과 유지가 가능했다.As a result, according to FIG. 6, a homogeneous and stable translucent colloidal nanoparticle dispersed phase was shown, and the average particle size tended to decrease around 100 nm as the concentration of the main component decreased. The pH, which is directly related to eye drops, was set to
점안제는 최대 1.5 중량%의 농도로 주성분을 가용화할 수 있었으며, 그 이하의 농도에서도 역시 안정하고 균질한 분산상의 점안제제의 제제화가 가능하였다. 주성분 농도에 따라서 평균입자크기가 감소하였고, 삼투압에서는 유의적인 차이를 나타내지 않았고 230 내지 250 mOsm 범위를 나타냈다.The eye drop was able to solubilize the main component at a concentration of up to 1.5% by weight, and even at a concentration lower than that, it was possible to formulate a stable and homogeneous dispersed eye drop preparation. The average particle size decreased according to the concentration of the main component, and the osmotic pressure did not show a significant difference and was in the range of 230 to 250 mOsm.
7. 나노이멀젼 점안제 안정성 시험7. Nanoemulsion eye drops stability test
상기 실시예에 의해 제조된 점안제제에서 최대 주성분 농도인 1.5 중량% 점안제제에 대하여 가속조건 (40 ℃)에서 6개월 (24주)동안 보관하며, 주요 항목에 대한 간이 안정성 시험을 실시했다.In the eye drop preparations prepared in the above example, the maximum concentration of the active ingredient, 1.5% by weight, was stored under accelerated conditions (40 ° C.) for 6 months (24 weeks), and a simple stability test was conducted for the main items.
그 결과, 도 7에 의할 때, 시험기간 동안 입자크기가 증가하고, 액성이 낮은 수준으로 산성화되는 경향성을 나타내었지만 안정성에 크게 영향을 미치는 수준은 아니며 설정 범위에 따라서 충분히 기준에 적합하다고 판단했다.As a result, according to FIG. 7, the particle size increased during the test period and the liquid tended to be acidified to a low level, but it was not a level that greatly affected the stability, and it was determined that it satisfies the standard sufficiently according to the set range. .
분해생성물 평가에서 주성분 피크 (%)가 6개월 동안 7 % 순감소 하였으나, 대부분 기지의 상기 표 1의 Impurity A 및 Impurity B로 분해되는 것이며, 이 정도 피크면적 감소는 유효기간 확보에 긍정적이며, Impurity A 및 Impurity B는 기지의 물질로서 독성 측면에서 뒷받침되면 그 기준한도를 상향할 수 있을 것으로 판단했다. 6개월간 특이적 침전이나 성상변화는 관찰되지 않았고, 미생물의 오염과 증식도 관찰되지 않았다. 아직 후보물질 평가단계 이지만 상용화를 위한 기본 중요 품질 특성을 갖춘 것으로 볼 수 있었다.In the evaluation of decomposition products, the main component peak (%) decreased by 7% netly for 6 months, but most of them were decomposed into the known Impurity A and Impurity B of Table 1 above. A and Impurity B are known substances, and it was determined that the standard limit could be raised if supported in terms of toxicity. No specific precipitation or change in properties was observed for 6 months, and no contamination or proliferation of microorganisms was observed. Although it is still in the candidate material evaluation stage, it could be seen as having basic important quality characteristics for commercialization.
[시험예 2] 다른 수난용성 약물에 대한 적용[Test Example 2] Application to other poorly water-soluble drugs
SH11037을 적용한 상기 실시예에 따른 점안제제를 다른 후보물질인 SH-17040, SH-17059, SH-19021, SHA-032, SHA-034 및 SH-17060에 적용하여 가용화및 제제화 특성에 대해서 평가했다. The eye drop preparation according to the above example using SH11037 was applied to other candidate materials, such as SH-17040, SH-17059, SH-19021, SHA-032, SHA-034 and SH-17060, and evaluated for solubilization and formulation characteristics.
그 결과, 표 4에 의할 때, 제시된 후보물질들은 1.5 중량%의 농도까지 가용화 할 수 있음을 확인했다. 제조상에서 특이 사항이 없이 SH11037 제제를 확대 적용할 수 있었다.As a result, according to Table 4, it was confirmed that the proposed candidates could be solubilized up to a concentration of 1.5% by weight. The SH11037 formulation was able to be expanded and applied without any special considerations in manufacturing.
ELCremophor
EL
ChlorideBenzalkonium
Chloride
(in 수상)DW
(in award)
또한, 상기 실시예와 동일한 첨가제 분량과 제조방법에 따라서 제조하여 주요 품질항목에 대하여 평가한 결과, 도 8에 의할 때, 분산 시에 침전 없이 안정하고 균일한 분산상을 얻을 수 있었고, 삼투성도 조절되었고, 평균입자크기도 모두 100 nm 이내의 값을 나타냈다. In addition, as a result of evaluating the main quality items by manufacturing according to the same amount of additives and manufacturing method as in the above example, as shown in FIG. , and the average particle size also showed values within 100 nm.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention.
Claims (11)
(b) 완충제, 등장화제, 보존제 및 물을 혼합한 후, pH 조절제를 가하여 pH 4.5 내지 6으로 조정하여 수상을 제조하는 단계;
(c) 상기 (a) 단계의 유상 혼합액에 상기 (b)단계의 수상 혼합액을 가하여 분산시켜 분산상을 제조하는 단계; 및
(d) 상기 (c) 단계의 분산상을 제균하는 단계;를 포함하는 pH 의존적 나노이멀젼 조성물 제조방법.(a) preparing an oil phase by mixing oils and a surfactant at a weight ratio of 1:1 to 3 and then adding and dissolving a poorly water-soluble drug at 55 to 65 °C;
(b) preparing an aqueous phase by mixing a buffer, an isotonic agent, a preservative and water, and then adding a pH adjusting agent to adjust the pH to 4.5 to 6;
(c) preparing a dispersed phase by adding and dispersing the aqueous phase mixture of step (b) to the oil phase mixture of step (a); and
(d) disinfecting the dispersed phase of step (c); pH-dependent nanoemulsion composition manufacturing method comprising the.
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| KR20210076903A (en) * | 2018-08-28 | 2021-06-24 | 클라우드브레이크 테라퓨틱스, 엘엘씨 | Emulsion formulations of multikinase inhibitors |
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| KR101492447B1 (en) * | 2013-05-20 | 2015-02-23 | 주식회사태준제약 | Eye composition containing a cyclosporine and a method of preparing the same |
| CN107257680A (en) * | 2015-03-05 | 2017-10-17 | 阿勒根公司 | Self-emulsifying drug delivery system (SEDDS) for ocular drug delivery |
| KR102435238B1 (en) * | 2019-04-24 | 2022-08-23 | 가천대학교 산학협력단 | chromane derivatives, and pharmaceutical composition for preventing or treating neovascular eye disease or cancer containing the same as an active ingredient |
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| KR20210076903A (en) * | 2018-08-28 | 2021-06-24 | 클라우드브레이크 테라퓨틱스, 엘엘씨 | Emulsion formulations of multikinase inhibitors |
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