대한안과학회지 2014 년제 55 권제 12 호 J Korean Ophthalmol Soc 2014;55(12):1745-1751 pissn: 0378-6471 eissn: 2092-9374 http://dx.doi.org/10.3341/jkos.2014.55.12.1745 Original Article 인공눈물점안제종류에따른의안표면습윤능비교 Comparison of Wettability for Ocular Prosthesis Depending on Different Kinds of Artificial Tear Eye Drops 장세란 윤일석 임헌섭 국경훈 Se Ran Jang, MD, Il Suk Yun, MD, Hun Sub Lim, MD, Koung Hoon Kook, MD, PhD 아주대학교의과대학안과학교실 Department of Ophthalmology, Ajou University School of Medicine, Suwon, Korea Purpose: In this study we compared the surface wettability of ocular prosthesis and depositions depending on different types of artificial tear eye drops. Methods: The artificial tear eye drops contain sodium hyaluronate (HA) 0.1%, 0.18%, 0.3%, carboxylmethylcellulose sodium (CMC), hydroxymethylcelluose + dextran (HMC), propylene glycol + polyethylene glycol (PG), polysorbate 80 (PS) povidone (Pov) were evaluated. Flat rectangular parallelepiped blocks consisting of polymethylmethacrylate (PMMA) or silicone materials were made. One artificial tear eye drop was applied on the surface of two different blocks of artificial eyes using a 23-gauge needle. Then, the static method contact angle was measured by using a contact angle goniometer. To measure the deposits, a petri dish was covered with 3 ml of artificial tear eye drops and dried for 48 hours at room temperature. Then, the light transmittance at the center of the petri dish was measured to investigate the amount of the residue. Results: The contact angles of HA 0.1%, 0.18%, 0.3%, CMC, HMC, PG, PS and Pov on PMMA were 78.69, 84.29, 75.46, 80.93, 66.29, 71.26, 58.40 and 70.24, respectively. The contact angles on silicone were 53.68, 60.87, 64.46, 62.78, 38.89, 63.58, 30.68 and 51.41, respectively. The largest decrease in transparency was observed in the artificial tear eye drops containing HMC. Conclusions: The wettability and deposits on the surface of ocular prosthesis can vary based on the components and concentration of artificial tear eye drops. The results from this study should be considered when choosing the right artificial tear eye drops for improving dry eye symptoms in patients wearing ocular prostheses. J Korean Ophthalmol Soc 2014;55(12):1745-1751 Key Words: Anophthalmos, Artificial tear eye drop, Dry eye syndrome, Ocular prosthesis, Wettability 건성안은매우흔한안과질환으로, 성인인구의약 10-20% 가건성안으로인한다양한정도의안구불편감, 시야흐림, Received: 2014. 4. 26. Revised: 2014. 5. 20. Accepted: 2014. 11. 5. Address reprint requests to Koung Hoon Kook, MD, PhD Department of Ophthalmology, Ajou University Medical Center, #164 World cup-ro, Yeongtong-gu, Suwon 443-380, Korea Tel: 82-31-219-5260, Fax: 82-31-219-5259 E-mail: drkook@ajou.ac.kr * This study was presented as a narration at the 110th Annual Meeting of the Korean Ophthalmological Society 2013. 시림등의증상을호소하는것으로알려졌다. 1 건성안의병리기전에따른치료로스테로이드, 면역억제제등의점안제가사용되고있으나, 부족한눈물의보충으로서인공눈물점안제의역할은건성안의건조증상에대한치료에기초가되고있다. 현재인공눈물점안제는매우다양한성분과농도의제제가시판되고있어환자특성및증상에따라적절한약제의선택이필요한데, 각각의점안제마다그효능이외에도점안시의자극감, 시야흐림, 끈적거림등의불편감의정도및그에따른환자의선호도등이중요한선 c2014 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1745
- 대한안과학회지 2014 년제 55 권제 12 호 - 택의기준이될수있을것이다. 한편, 여러가지눈의질환, 산업재해, 혹은교통사고를비롯한눈의외상으로인해안구를잃게되는경우에안구를제거하고자연스러운모습을위해의안을착용하게되며, 의안을착용한환자들도뻑뻑함, 쓰라림, 눈꺼풀이무거운느낌등일반적인건성안증상을호소하게된다. 2 따라서의안착용환자들도인공눈물점안제를사용하게되는데, 점안제의선택에있어정상안과는다른특성을고려하여야할것이다. 하지만, 정상안에서는어떠한성분의인공눈물점안제가더효과적인지에대한여러연구가발표되어있는데반해, 3,4 의안착용환자들에있어인공눈물점안제의선택에도움이될수있는연구는지금까지없었다. 의안착용환자에서는정상안환자들과비교하여각막의부재와연관된안표면감각의차이로인해점안으로인한자극감의정도가덜할수있겠으며, 점안후시야흐림의문제를고려할필요가없을것이다. 오히려의안착용환자에서이상적인인공눈물점안제가가져야할특성으로는, 의안표면을고루적셔건조증상을효과적으로해결할수있어야한다는점과, 의안착용으로정상적인눈깜박임에의한눈물배출이적절치못한경우에인공눈물이결막낭또는의안표면에정체되는경우의안표면에잔류물이남아일으킬수있는미용적문제가최소화되어야한다는점일것으로생각할수있겠다. 인공눈물점안제가의안표면을고루적실수있는정도는습윤능으로표현할수있겠으며, 습윤능이란고체표면에액체가퍼지는경향으로정의할수있고, 5-7 습윤능을확인하기위한방법으로접촉각측정이보편적으로사용되고있다. 8-10 접촉각이란액체가고체표면위에서열역학적으로평형을이룰때이루는각을의미하며, 이때작은접촉각은높은습윤능을, 큰접촉각은낮은습윤능을가진다고해석된다. 이러한습윤능의차이는액체자체의속성뿐아 니라고체와의열역학적관계에의해결정되므로의안재질에따라서도각인공눈물점안제의접촉각즉, 습윤능이달라질수있을것이다. 따라서본연구에서는, 흔히사용되는의안의재질인폴리메틸메타크릴레이트 (Polymethyl-methacrylate, PMMA) 와실리콘표면에대한여러인공눈물점안제의습윤능을비교함으로써의안착용환자들의인공눈물점안제선택에도움이되고자하였다. 아울러앞서기술한바와같이, 의안표면에점안제의잔류물이남을경우잔류물의불투명성에의한미용적인문제도발생가능할것이므로이에대한연구도포함하여시행하였다. 대상과방법 현재시판되고있는인공눈물점안제중성분및농도별로 8가지의점안제를선정하였다 (Table 1). 습윤능측정을위해서일반적인의안제작방법에따라 11 PMMA 재질과실리콘재질의편평한직육면체블록을제작한뒤 (Fig. 1), 23 게이지바늘이달린 3 cc 주사기에선정된인공눈물점안제를채우고의안블록표면에한방울 ( 약 9 µl) 씩점적하였다. 접촉각측정기 (Contact angle goniometer, Phoenix PMMA Silicone Figure 1. Two flat rectangular parallelepiped blocks. According to the conventional methods of manufacturing of ocular prosthesis, two blocks have been produced with polymethylmethacrylate (PMMA) or silicone. Table 1. Selected artificial tear eye drops Artificial tears Abbreviation Trade name, manufacturer Hyaluronate base Sodium hyaluronate 0.1% HA 0.1 Hyalein mini 0.1%, Santen Sodium hyaluronate 0.18% HA 0.18 Hyalu mini 0.18%, Hanmi Sodium hyaluronate 0.3% HA 0.3 Hyaluni 0.3%, Taejoon Methylcelluose base Carboxylmethylcellulose sodium CMC Refresh plus, Samil-Allergan Hydroxymethylcelluose + dextran HMC Tears naturale free, Alcon Others Propylene glycol + polyethylene glycol PG Systane, Alcon Polysorbate 80 PS Eyedew, JW Shinyak Povidone Pov Optagent, Samil-Allergan HA = hyaluronate; CMC = carboxylmethylcellulose sodium; HMC = hydroxymethylcelluose + dextran; PG = propylene glycol + polyethylene glycol; PS = polysorbate 80; Pov = povidone. 1746
- 장세란외 : 인공눈물점안제의의안표면습윤능 - 150, SEO, Gyunggido, Korea) 를이용하여정적앉은방울방법 (Static sessile drop method) 으로 12 블록위에서의인공눈물점안제방울이미지를각각의조합에서 5장씩촬영하였으며, 촬영은점적후 5초뒤에시행하였다. 점안제의종류와블록재질에대해정보를가지지않은검사자에의해 Image J (National Institutes of Health, NIH) 프로그램을이용하여앞서촬영한이미지에서보이는접촉각을측정하였고 (Fig. 2), 최고, 최저각도를제외한중간값측정치 3개의평균을기록하였다. 잔류물측정을위해서, 직경 60 mm의페트리접시에그표면을균일한두께로덮을수있도록인공눈물점안액 3 ml를각각도포하고상온에서 48시간건조시켰다. 각각의페트리접시를육안으로관찰하여비교하였고, 광학분광기 (Lambda 950, Perkin Elmer, Massachusetts, U.S.A.) 를이용하여페트리접시의중앙부위에서 15 mm 5 mm 크기의샘플빔을통한가시광선파장대 (330-770 nm) 의투과율을측정및비교하였다. 페트리접시자체의투과율에의한오 차를최소화하기위해페트리접시덮개의투과율을측정하여이를보정하였다. 결과 PMMA와실리콘재질모두에서각각의인공눈물점안제는다양한접촉각을나타냈으며 (Fig. 3, Table 2), polysorbate 80 성분의점안제가두재질모두에서각각 58.40 와 30.68 의접촉각으로가장우수한습윤능을보였다. 그외에도 Hydroxymethylcelluose+Dextran, Povidone성분의점안제가두재질모두에서상대적으로우수한습윤능을나타내었다. 모든점안제가 PMMA 재질보다실리콘재질에서접촉각이작게측정되어, 동일한점안제라면실리콘재질의의안이 PMMA 재질의의안보다더우월한습윤능을보임을알수있었다. 육안으로관찰한잔류물검사결과, 다른성분의인공눈물점안제에비하여 Hydroxymethylcelluose+Dextran성분점안제의잔류물이현저하게많았다 (Fig. 4). 가시광선파장대의빛투과율또한, 다른성분의점안제는 0.97에서 0.63 으로측정되었으나 Hydroxymethylcelluose+Dextran성분점안제는 0.01의투과율을보여잔류물에의한투과율저하가가장심하였다 (Fig. 5, Table 3). Figure 2. Measurement of contact angle. The contact angle is an angle formed between the liquid/solid interface and the liquid/vapor interface. 고 찰 의안을착용한환자들도건성안에의한다양한불편감을 Figure 3. Images obtained from a contact angle goniometer. One drop of each artificial tear eye drops was applied on polymethylmethacrylate (PMMA) or silicone block. CMC = carboxylmethylcellulose sodium; HMC = hydroxymethylcelluose + dextran; PG = propylene glycol + polyethylene glycol; PS = polysorbate 80; Pov = povidone. Table 2. Contact angles of artificial tear eye drops on PMMA or silicone block ( ) Hyaluronate Methylcellulose Others 0.1% 0.18% 0.3% CMC HMC PG PS Pov PMMA 78.69 84.29 75.46 80.93 66.29 71.26 58.40 70.24 Silicone 53.68 60.87 64.46 62.78 38.89 63.58 30.68 51.41 PMMA = polymethylmethacrylate; CMC = carboxylmethylcellulose sodium; HMC = hydroxymethylcelluose + dextran; PG = propylene glycol + polyethylene glycol; PS = polysorbate 80; Pov = povidone. 1747
- 대한안과학회지 2014년 제 55 권 제 12 호 - HA 0.1 HA 0.18 HMC CMC PG PS HA 0.3 Pov Figure 4. The residues of each artificial tear eye drops in petri dishes. After evaporation, the HM C containing artificial tear eye drops showed the most residues on the petri dish. HA = hyaluronate; HM C = hydroxymethylcelluose + dextran; CM C = carboxylmethylcellulose sodium; PG = propylene glycol + polyethylene glycol; PS = polysorbate 80; Pov = povidone. 호소하게 되는데, 실제로 Kim et al2은 정상안과 비교하여 반사 눈물이 없기 때문이라고 설명하였으며, 의안을 착용 무안구안이 건성안 증상을 더 심하게 호소하고 있으며 퓨리 한 환자들의 50%가 이러한 눈물 부족을 경험하고 있다고 어 영역 빛간섭단층촬영(Fourier-Domain Optical Coherence 하였다. 의안에 의한 눈꺼풀판의 자극, 토안, 불완전한 눈깜 Tomography)을 이용하여 측정한 눈물띠 두께와 눈물띠 높 박임 등에 의해 발생하는 마이봄샘의 기능부전도 의안 착 이가 정상안보다 무안구안에서 더 얕고, 더 낮은 것을 확인 용 환자들에서 나타나는 건성안의 원인 중 하나로 보고되 13 하였다. 또한, Allen et al 의 연구에서 무안구 환자를 대상 었다.14 무안구안에서의 눈물부족은 눈물의 구성을 변화시 으로 쉬르머I, II 검사를 시행한 결과, 정상안에 비하여 눈 키며 이는 결막의 염증을 유발하여 점막의 각질화, 점성 분 물분비가 적은 것을 확인하였는데 이는 각막 부재로 인해 비물 생성, 결막낭의 수축을 초래하고, 결국에는 반흔성 눈 1748
- 장세란외 : 인공눈물점안제의의안표면습윤능 - Table 3. Relative transmittance through the residue of artificial tear eye drops Control Hyaluronate Methylcellulose Others Petri dish 0.1% 0.18% 0.3% CMC HMC PG PS Pov 1.00 0.66 0.97 0.69 0.74 0.01 0.63 0.80 0.70 CMC = carboxylmethylcellulose sodium; HMC = hydroxymethylcelluose + dextran; PG = propylene glycol + polyethylene glycol; PS = polysorbate 80; Pov = povidone. Figure 5. Transmittance through the residue of artificial tear eye drops. After drying of each eye drop on petri dishes, the transmittance was measured by spectrometer. A double head arrow indicates the visible light wavelength range (330-770 nm). HA = hyaluronate; HMC = hydroxymethylcelluose + dextran; CMC = carboxylmethylcellulose sodium; PG = propylene glycol + polyethylene glycol; PS = polysorbate 80; Pov = povidone. 꺼풀속말림을야기할수있다. 15 따라서건성안의적절한치료를통해만성적인염증에의한눈꺼풀및결막낭의변화를예방할수있을것이라는점에서의안착용환자들에게적절한인공눈물점안제의사용은매우중요한문제라고할수있다. 습윤능이란어떤액체가고체표면위로퍼지는경향으로정의할수있다. 5-7 습윤능을측정하는가장보편적인방법은접촉각을측정하는것인데, 본연구에서는가장간단하면서도재현성이높은것으로알려져있는정적앉은방울방법 (static sessile drop method) 16 을이용해접촉각을측정하였다. 접촉각측정에영향을미치는요인으로는측정시의온도, 액체와고체의접촉후측정까지의시간, 고체표면의거칠기, 액체방울의부피등이있다. 16,17 본연구에서는온도와습도가일정하게유지되는실험실에서측정을시행하였고인공눈물점안제방울을의안재질블록표면에올려놓은후 5초가지난시점으로측정시기를통일하였다. 실제의안을사용해실험할경우, 의안의곡면에방울이놓인위치가일정치못할경우경사로인한접촉각의편차가발생할수있음을고려하여곡면을가진실제의안대신의안재질로편평한블록을제작하였다. 그리고액체방울의부피가 10 µl 이하일경우액체방울의부피의비 균일성으로인한접촉각의오류는거의없는것으로보고되어있으므로, 18,19 실험시약 9 µl의인공눈물점안제방울을사용하였으며, 점안제의종류와블록재질에대해정보를가지지않은 1명의실험자가 5번의측정을시행하여최대, 최소값을제외한 3개측정치의평균을구함으로써오차를최소화하였다. 이미지를이용하여접촉각을측정하는경우, 20 미만의접촉각에서는결과가부정확할수있다고알려졌으나, 20 본실험결과에서는모든결과값이 20 이상이었으므로본연구결과를신뢰할수있을것으로생각한다. 그외에도, 특정액체와고체의접촉각을결정하는인자로액체의수소결합비율, 액체의점성, 액체와고체의친화도등이알려졌다. 21 본연구에서는각인공눈물점안제들의의안표면에대한습윤능이차이를보인다는점을확인하였지만, 습윤능과양의혹은음의상관관계를보이는점안제의특정성분혹은그특성에대한규명은본연구내용에포함되지는않았다. 추후이에대한연구가진행될수있을것으로생각한다. 잔류물에대한실험에서는 Hydroxymethylcelluose+Dextran 성분의점안제를건조시킨페트리접시의투과율이가장낮았고 Sodium hyaluronate 0.18% 성분의점안제를건조시킨페트리접시의투과율이가장높았으며, 이는육안으로관찰하였을때도확연한차이를보였다. 즉, 의안착용환자에서 Hydroxymethylcelluose+Dextran 성분의점안제를장기간점안하였을때, 점안제의잔류물이적절히코눈물관등을통해배출되거나의안을적절하게세척하지않는다면다른인공눈물점안제에비해육안으로확인될만한잔류물을남기게되어의안의투명도저하등의미용적문제를일으킬수있을것이다. 하지만이는실험적인결과로실제로눈깜박임이불완전하고눈물배출이원활하지않은의안착용환자라할지라도점안된약제가온전히의안표면에잔류물을남기지는않을것으로예상해볼수도있겠다. 그러나, 실험에사용된점안제의양이 3 ml이며실제시판되는약제들의포장용량이 1회용점안제인경우 0.4-0.9 ml, 병포장인경우 5 ml 정도인것을고려할때장기간사용하게되는인공눈물점안제의특성상잔류물의영향을완전히무시하기는어려울것으로생각한다. 또한, 본연구에서실행한방법인페트리접시에건조시킨상황과달리실제환자들에서는눈물로인해점안제성분이씻겨지고 1749
- 대한안과학회지 2014 년제 55 권제 12 호 - 의안을관리및세척하게되므로, 추후연구에서는잔류물과의안재질표면간의부착정도또는친화도를측정하는것이도움이될것으로생각한다. 의안착용환자들의실제임상상황과본연구의실험디자인을비교해볼때, 의안표면은곡면이며, 점안시중력의영향을받고, 눈깜박임이있다는점에서본연구에서실험한상황과다르며이는연구결과를곧바로임상상황에서의안표면의습윤능을나타낸다고보는데있어제한점으로작용할수있다. 하지만본연구를통해규명된서로다른인공눈물점안제간의의안재질표면에대한습윤능및잔류물정도의차이를토대로, 추후의안착용환자들을위한인공눈물점안제선택에도움을줄수있을것으로생각한다. 향후, 특정점안제의습윤능과건성안증상호전정도의상관관계에관한연구나, 분자량, 분자구조, 오스몰농도, 산성도, 끓는점, 점성등인공눈물점안제의특성과습윤능과의상관관계에대한연구, 그리고실제의안착용후인공눈물점안제를일정기간점안하였을때의안표면에잔존하는잔류물의정도에대한연구가시행될수있을것으로생각한다. REFERENCES 1) Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J 1995;21:221-32. 2) Kim SE, Yoon JS, Lee SY. Tear measurement in prosthetic eye users with fourier-domain optical coherence tomography. Am J Ophthalmol 2010;149:602-7.e1. 3) Aragona P, Papa V, Micali A, et al. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol 2002;86:181-4. 4) Asbell PA. Increasing importance of dry eye syndrome and the ideal artificial tear: consensus views from a roundtable discussion. Curr Med Res Opin 2006;22:2149-57. 5) Carré A, Woehl P. Spreading of silicone oils on glass in two geometries. Langmuir 2006;22:134-9. 6) Churaev NV, Sobolev VD. Wetting of low-energy surfaces. Adv Colloid Interface Sci 2007;134-5:15-23. 7) Molina R, Comelles F, Juliá MR, Erra P. Chemical Modifications on Human Hair Studied by Means of Contact Angle Determination. J Colloid Interface Sci 2001;237:40-6. 8) Tonge S, Jones L, Goodall S, Tighe B. The ex vivo wettability of soft contact lenses. Curr Eye Res 2001;23:51-9. 9) Cheng L, Muller SJ, Radke CJ. Wettability of silicone-hydrogel contact lenses in the presence of tear-film components. Curr Eye Res 2004;28:93-108. 10) Ketelson HA, Meadows DL, Stone RP. Dynamic wettability properties of a soft contact lens hydrogel. Colloids Surf B Biointerfaces 2005;40:1-9. 11) Raizada K, Rani D. Ocular prosthesis. Cont Lens Anterior Eye 2007;30:152-62. 12) Adler M, Miller R, Weaire D. Advances in colloid and interface science. Foreword. Adv Colloid Interface Sci 2008;137:1. 13) Allen L, Kolder HE, Bulgarelli EM, Bulgarelli DM. Artificial eyes and tear measurements. Ophthalmology 1980;87:155-7. 14) Jang SY, Lee SY, Yoon JS. Meibomian gland dysfunction in longstanding prosthetic eye wearers. Br J Ophthalmol 2013;97:398-402. 15) Saedon H, Cheung D. Occult traumatic nasolacrimal duct obstruction causing anophthalmic socket contraction presenting 20 years later: a case report. Cutan Ocul Toxicol 2008;27:87-9. 16) Read ML, Morgan PB, Kelly JM, Maldonado-Codina C. Dynamic contact angle analysis of silicone hydrogel contact lenses. J Biomater Appl 2011;26:85-99. 17) Chau TT, Bruckard WJ, Koh PT, Nguyen AV. A review of factors that affect contact angle and implications for flotation practice. Adv Colloid Interface Sci 2009;150:106-15. 18) Yang J, Rose FR, Gadegaard N, Alexander MR. Effect of sessile drop volume on the wetting anisotropy observed on grooved surfaces. Langmuir 2009;25:2567-71. 19) Taylor M, Urquhart AJ, Zelzer M, et al. Picoliter water contact angle measurement on polymers. Langmuir 2007;23:6875-8. 20) Yuan Y, Lee TR. Contact angle and wetting properties. Surface Science Techniques. Springer Berlin Heidelberg 2013;51:3-34. 21) Dutcher CS, Wexler AS, Clegg SL. Surface tensions of inorganic multicomponent aqueous electrolyte solutions and melts. J Phys Chem A 2010;114:12216-30. 1750
- 장세란외 : 인공눈물점안제의의안표면습윤능 - = 국문초록 = 인공눈물점안제종류에따른의안표면습윤능비교 목적 : 인공눈물점안제의종류에따른의안표면에서의습윤능및잔류물정도의차이를확인하고자하였다. 대상과방법 : 시중에시판되는인공눈물점안제중, Sodiumhyaluronate (HA) 0.1%, 0.18%, 0.3%, Carboxylmethylcellulose sodium (CMC), Hydroxymethylcelluose+Dextran (HMC), Propylene glycol+polyethylene glycol (PG), Polysorbate 80 (PS), Povidone (Pov) 성분의점안제를연구대상으로선정하여, 폴리메틸메타크릴레이트 (Polymethylmethacrylate, PMMA) 재질과실리콘재질의블록표면에각각한방울씩떨어뜨린후접촉각을측정하였다. 잔류물측정은투명한페트리접시에점안제를도포하고상온에서건조시킨후빛투과율을측정하였다. 결과 : PMMA 재질의블록표면에서의접촉각은 HA 0.1%, 0.18%, 0.3%, CMC, HMC, PG, PS, Pov 성분의점안제가순서대로 78.69, 84.29, 75.46, 80.93, 66.29, 71.26, 58.40, 70.24 이었으며, Silicone 재질의표면에서는 53.68, 60.87, 64.46, 62.78, 38.89, 63.58, 30.68, 51.41 이었다. 빛투과율의저하는 HMC 성분의점안제가가장심하였다. 결론 : 인공눈물점안제에따라습윤능및잔류물에차이가있으며, 의안착용환자에서인공눈물점안제선택시이를고려할수있겠다. < 대한안과학회지 2014;55(12):1745-1751> 1751