| Sains Malaysiana 52(6)(2023):
          
        1671-1683 http://doi.org/10.17576/jsm-2023-5206-05
            
           
             
           Activity and
            Safety of Cinchonine Nanostructured Lipid Carriers as a Hair Growth Stimulant
            in Mice Model of Androgenetic Alopecia
              
             (Aktiviti dan Keselamatan Pembawa Lipid Berstruktur
            Nano Sinkonina sebagai Perangsang Pertumbuhan Rambut dalam Model Tikus Alopecia
            Androgenetik)
            
           
             
           HARIYANTI
            HARIYANTI1,2, RACHMAT MAULUDIN1, YEYET CAHYATI
            SUMIRTAPURA1 & NENG FISHERI KURNIATI3,*
            
           
             
           1Department of Pharmaceutic,
            School of Pharmacy, Institut Teknologi Bandung, Bandung, West Java, 40132,
            Indonesia
            
           2Department of Pharmaceutical, Faculty of Pharmacy,
            Universitas Muhammadiyah Purwokerto, Purwokerto, Central Java, 53182,
            Indonesia  
            
           3Department of Pharmacology-Clinical Pharmacy, School
            of Pharmacy, Institut Teknologi Bandung, Bandung, West Java, 40132, Indonesia
            
           
             
           Diserahkan: 21 Februari 2022/Diterima: 9 Jun 2023
            
            
            
           Abstract
            
           Androgenetic
            alopecia (AA) is a hair growth disorder characterized by hair loss and
            miniaturization of the size of follicles and dermal papillae. Cinchonine is a
            quinoline alkaloid that can increase VEGF production and potential as a hair
            growth stimulant. This study aimed to determine the morphology, penetration (in
              vitro), as well as safety and activity of cinchonine nanostructured lipid
            carriers (CN-NLC) serum as a hair growth stimulant. Preparation of CN-NLC serum
            using a combination of micro-emulsification and ultra-sonification methods,
            characterization of CN-NLC serum included morphology and closed hair follicle
            diffusion methods.
              Dermal and eye irritation test using New Zealand rabbit strain with primary
              irritation index parameters. Hair growth stimulant activity test using Swiss
              Webster mice strain, induced with the hormone testosterone. Observations were
              performed at 7, 14, and 21 days with hair length and histology parameters.
              CN-NLC serum morphology is a spherical shape with size ±500 nm, diffusion of
              serum CN-NLC (open hair follicles) of 23.92±0.84%; (close hair follicles) of
              11.37±2.29%; and CN solution of 6.00±0.72%. CN-NLC serum are non-irritant with
              a primary irritation index of 0.0. Activity tests showed hair length on days 7;
              14 and 21 were increased by 20.24-23.74%; 33.47-36.43%, and 39.30-39.97%
              (P≤0.05). Histological data showed an increase in the number and size of
              both dermal papillae and hair follicles compared to the control group. CN-NLC
              serum can improve the penetration of CN into hair follicles. CN-NLC serum is
              safe and effective as a hair growth stimulant in the treatment of AA.
              
             
             
           Keywords: Androgenic alopecia; cinchonine; nanostructured lipid
            carriers 
            
           
             
           Abstrak
            
           Alopecia
            androgenetik (AA) adalah gangguan pertumbuhan rambut yang dicirikan oleh
            keguguran rambut dan pengecilan saiz folikel dan papila dermal. Sinkonina
            adalah alkaloid kuinolina yang boleh meningkatkan pengeluaran VEGF dan
            berpotensi sebagai perangsang pertumbuhan rambut. Kajian ini bertujuan untuk
            menentukan morfologi, penembusan (in vitro), serta keselamatan dan
            aktiviti serum pembawa lipid berstruktur nano (CN-NLC) sinkonina sebagai
            perangsang pertumbuhan rambut. Penyediaan serum CN-NLC menggunakan gabungan
            kaedah pengemulsi mikro dan ultra-sonifikasi, pencirian serum CN-NLC termasuk
            kaedah morfologi dan kaedah penyebaran folikel rambut tertutup. Ujian
            kerengsaan kulit dan mata menggunakan ketegangan arnab New Zealand dengan
            parameter indeks kerengsaan primer. Ujian aktiviti perangsang pertumbuhan
            rambut menggunakan ketegangan tikus Swiss Webster, diinduksi dengan hormon
            testosteron. Pemerhatian dilakukan pada 7, 14 dan 21 hari dengan panjang rambut
            dan parameter histologi. Morfologi serum CN-NLC ialah bentuk sfera dengan saiz
            ±500 nm, resapan serum CN-NLC (folikel rambut terbuka) sebanyak 23.92±0.84%;
            (folikel rambut tertutup) sebanyak 11.37±2.29%; dan larutan CN sebanyak
            6.00±0.72%. Serum CN-NLC tidak merengsa dengan indeks kerengsaan primer 0.0.
            Ujian aktiviti menunjukkan panjang rambut pada hari ke-7; 14 dan 21 meningkat
            sebanyak 20.24-23.74%; 33.47-36.43% dan 39.30-39.97% (P≤0.05). Data
            histologi menunjukkan peningkatan dalam bilangan dan saiz kedua-dua papila
            dermal dan folikel rambut berbanding kumpulan kawalan. Serum CN-NLC dapat
            meningkatkan penembusan CN ke dalam folikel rambut. Serum CN-NLC selamat dan
            berkesan sebagai perangsang pertumbuhan rambut dalam rawatan AA.
            
           
             
           Kata
            kunci: Alopecia androgenetik; pembawa lipid berstruktur nano; sinkonina
            
           
             
           RUJUKAN
            
           
            
            Abd,
              E., Benson, H.A.E., Roberts, M.S. & Grice, J.E. 2018. Follicular
              penetration of caffeine from topically applied nanoemulsion formulations containing
              penetration enhancers: in vitro human skin studies. Skin Pharmacology
                and Physiology 31(5): 252-260. https://doi.org/10.1159/000489857
              
             Blume-Peytavi, U., Varvar, K. & Vogt, A. 2016. The
            Alopecias Diagnosis and Treatments, edited by Bouhanna, P. & Bouhanna,
            E. Boca Raton: CRC Press.
            
           Blume-Peytavi,
            U., Tosti, A., Whiting, D.A. & Trüeb, R.M. 2008. Hair Growth and
              Disorders. Hair. Springer. https://doi.org/10.1007/978-3-540-46911-7
            
           Bubić
            Pajić, N., Ilić, T., Nikolić, I., Dobričić, V.,
            Pantelić, I. & Savić, S. 2019. Alkyl Polyglucoside-Based
            Adapalene-Loaded Microemulsions for Targeted Dermal Delivery: Structure,
            Stability and Comparative Biopharmaceutical Characterization with a
            Conventional Dosage Form. Journal of Drug Delivery Science and Technology 54. https://doi.org/10.1016/j.jddst.2019.101245
            
           Chen,
            Y., Feng, X., Zhao, Y., Zhao, X. & Zhang, X. 2020. Mussel-inspired
            polydopamine coating enhances the intracutaneous drug delivery from
            nanostructured lipid carriers dependently on a follicular pathway. Molecular
              Pharmaceutics 17(4): 1215-1225.
            https://doi.org/10.1021/acs.molpharmaceut.9b01240
            
           Driskell,
            R.R., Clavel, C., Rendl, M. & Watt, F.M. 2011. Hair follicle dermal papilla
            cells at a glance. Journal of Cell Science 124(8): 1179-1182.
            https://doi.org/10.1242/jcs.082446
            
           Fresta,
            M., Mancuso, A., Cristiano, M.C., Urbanek, K., Cilurzo, F., Cosco, D., Iannone,
            M. & Paolino, D. 2020. Targeting of the pilosebaceous follicle by liquid
            crystal nanocarriers: in vitro and in vivo effects of the
            entrapped minoxidil. Pharmaceutics 12(11): 1127.
            https://doi.org/10.3390/pharmaceutics12111127.
            
           Fu,
            D., Huang, J., Li, K., Chen, Y., He, Y., Sun, Y., Guo, Y., Du, L., Qu, Q.,
            Miao, Y. & Hu, Z. 2021. Dihydrotestosterone-induced hair regrowth
            inhibition by activating androgen receptor in C57BL6 mice simulates
            androgenetic alopecia. Biomedicine and Pharmacotherapy 137: 111247.
            https://doi.org/10.1016/j.biopha.2021.111247
            
           Gorzelanny,
            C., Mess, C., Schneider, S.W., Huck, V. & Brandner, J.M. 2020. Skin
            barriers in dermal drug delivery: Which barriers have to be overcome and how
            can we measure them? Pharmaceutics.
            https://doi.org/10.3390/pharmaceutics12070684
            
           Hariyanti,
            H., Sophi Damayanti & Sasanti Tarini Darijanto. 2020. Formulation and
            Activity test of cinchonine niosomesas hair growth stimulants. In EBSCO
              Industries, Inc. Vol. Suppl, p. 47.
            
           Hariyanti,
            H., Kurniati, N.F., Sumirtapura, Y.C. & Mauludin, R. 2023. Development and
            validation of an analytical method for the determination of nanostructured
            lipid carrier’s cinchonine used direct method modified by liquid-liquid
            extraction using high-performance liquid chromatography. Journal of Research
              in Pharmacy 27(2): 913-923. https://doi.org/10.29228/jrp.371
            
           Hariyanti,
            H., Mauludin, R., Sumirtapura, Y.C. & Kurniati, N.F. 2022. A review:
            Pharmacological activities of quinoline alkaloid of Cinchona sp. Biointerface
              Research in Applied Chemistry 13(Issue 4): 3.
            https://doi.org/org/10.33263/BRIAC134.319
            
           Inaba,
            M. & Inaba, Y. 1996. Therapy for androgenetic alopecia. In Androgenetic
              Alopecia. Tokyo: Springer. https://doi.org/10.1007/978-4-431-67038-4_25.
            
           Jeong,
            G., Shin, S.H., Kim, S.N., Na, Y., Park, B.C., Cho, J.H., Park, W-S. & Kim,
            H-J. 2022. Ginsenoside Re Prevents 3-Methyladenine-induced catagen phase
            acceleration by regulating Wnt/β-catenin signaling in human dermal papilla
            cells. Journal of Ginseng Research 47(3): 440-447.
            https://doi.org/https://doi.org/10.1016/j.jgr.2022.11.002
            
           Jimenez,
            W., Gonzalez, E., Murphy, V.A. & Bauta, W. 2021. Evaluation of dermal
            corrosion and irritation by cytoreg in rabbits. Toxicology Reports 8:
            1527-1529. https://doi.org/10.1016/j.toxrep.2021.07.021
            
           Joshi,
            M.D., Prabhu, R.H. & Patravale, V.B. 2019. Fabrication of nanostructured
            lipid carriers (NLC)-based gels from microemulsion template for delivery through
            skin. In Methods in Molecular Biology 2000: 279-292.
            https://doi.org/10.1007/978-1-4939-9516-5_19
            
           Kakadia,
            P.G. & Conway, B.R. 2018. Solid lipid nanoparticles for targeted delivery
            of triclosan into skin for infection prevention. Journal of Microencapsulation 35(7-8): 695-704. https://doi.org/10.1080/02652048.2019.1576796
            
           Kharat,
            M. & McClements, D.J. 2019. Fabrication and characterization of
            nanostructured lipid carriers (NLC) using a plant-based emulsifier: Quillaja
            Saponin. Food Research International 126: 108601.
            https://doi.org/10.1016/j.foodres.2019.108601
            
           Kim,
            J.H., Na, J., Bak, D‑H., Lee, B.C., Lee, E., Choi, M.J., Ryu, C.H., Lee,
            S., Mun, S.K., Park, B.C., Kim, B.J. & Lee, H.S. 2019a. Development of
            Finasteride Polymer Microspheres for Systemic Application in Androgenic
            Alopecia. International Journal of Molecular Medicine 43(6): 2409-2419.
            https://doi.org/10.3892/ijmm.2019.4149
            
           Kim,
            M.H., Kim, K.T., Sohn, S.Y., Lee, J.Y., Lee, C.H., Yang, H., Lee, B.K., Lee,
            K.W. & Kim, D.D. 2019b. Formulation and evaluation of nanostructured lipid
            carriers (NLCs) of 20(s)-protopanaxadiol (PPD) by box-behnken design. International
              Journal of Nanomedicine 14: 8509-8520. https://doi.org/10.2147/IJN.S215835.
            
           Kim,
            S.H., Park, M.K., Seol, J.K., Im, J.M., Park, H.S., Seo, H.S., Park, H.J. &
            Nah, S.S. 2021. Evaluation of potential eye or skin irritation/corrosion in
            rabbit exposed to Tio2 photocatalyst (GST). Environmental Health
              and Toxicology 36(3): e2021022-0. https://doi.org/10.5620/eaht.2021022
            
           Lademann,
            J., Darvin, M.E., Meinke, M.C. & Patzelt, A. 2019. Characterization of
            penetration of particles after dermal application. In Nanocosmetics,
            edited by Cornier, J., Keck, C., van de Voorde, M. Springer, Cham.
            https://doi.org/10.1007/978-3-030-16573-4_11
            
           Lademann,
            J., Knorr, F., Richter, H., Jung, S., Meinke, M.C., Rühl, E., Alexiev, U.,
            Calderon, M. & Patzelt, A. 2015. Hair follicles as a target structure for
            nanoparticles. Journal of Innovative Optical Health Sciences 8(4):
            1530004. https://doi.org/10.1142/S1793545815300049
            
           Lademann,
            J., Richter, H., Teichmann, A., Otberg, N., Blume-Peytavi, U., Luengo, J.,
            Weiss, B., Schaefer, U.F., Lehr, C-M., Wepf, R. & Sterry, W. 2007.
            Nanoparticles - An efficient carrier for drug delivery into the hair follicles. European Journal of Pharmaceutics and Biopharmaceutics 66(2): 159-164.
            https://doi.org/10.1016/j.ejpb.2006.10.019
            
           Leveque,
            M., Mas, C., Haure, M., Lejeune, O., Duplan, H., Castex-Rizzi, N. &
            Bessou-Touya, S. 2021. 601 hair growth properties of Cinchona succirubra extract, Leontopodium alpinum extract and manganese pca in human hair
            follicle dermal papilla cells. Journal of Investigative Dermatology 141(5): S104. https://doi.org/10.1016/j.jid.2021.02.629
            
           Melincovici,
            C.S., Boşca, A.B., Şuşman, S., Mărginean, M., Mihu, C.,
            Istrate, M., Moldovan, I.M., Roman, A.L. & Mihu, C.M. 2018. Vascular
            endothelial growth factor (VEGF) - Key factor in normal and pathological
            angiogenesis. Romanian Journal of Morphology and Embryology 59(2):
            455-467.
            
           Mohd,
            F., Todo, H., Yoshimoto, M., Eddy Yusuf & Sugibayashi, K. 2016.
            Contribution of the hair follicular pathway to total skin permeation of
            topically applied and exposed chemicals. Pharmaceutics 8(4): 32.
            https://doi.org/10.3390/pharmaceutics8040032
            
           Ou,
            H.C., Keating, S., Wu, P., Simon, J.A., Raible, D.W. & Rubel, E.W. 2012.
            Quinoline ring derivatives protect against aminoglycoside-Induced hair cell
            death in the zebrafish lateral line. JARO - Journal of the Association for
              Research in Otolaryngology 13(6): 759-770. https://doi.org/10.1007/s10162-012-0353-0
            
           Patzelt,
            A. & Lademann, J. 2020. Recent advances in follicular drug delivery of
            nanoparticles. Expert Opinion on Drug Delivery 17(1): 49-60.  https://doi.org/10.1080/17425247.2020.1700226.
            
           Pereira,
            M.N., Tolentino, S., Pires, F.Q., Anjos, J.L.V., Alonso, A., Gratieri, T.,
            Cunha-Filho, M. & Gelfuso, G.M. 2021. Nanostructured lipid carriers for
            hair follicle-targeted delivery of clindamycin and rifampicin to hidradenitis
            suppurativa treatment. Colloids and Surfaces B: Biointerfaces 197:
            111448. https://doi.org/10.1016/j.colsurfb.2020.111448
            
           Pires,
            F.Q., da Silva, J.K.R., Sa-Barreto, L.L., Gratieri, T., Gelfuso, G.M. &
            Cunha-Filho, M. 2019. Lipid nanoparticles as carriers of cyclodextrin inclusion
            complexes: A promising approach for cutaneous delivery of a volatile essential
            oil. Colloids and Surfaces B: Biointerfaces 182: 110382.
            https://doi.org/10.1016/j.colsurfb.2019.110382
            
           Rooney,
            J.P., Choksi, N.Y., Ceger, P., Daniel, A.B., Truax, J., Allen, D. &
            Kleinstreuer, N. 2021. Analysis of variability in the rabbit skin irritation
            assay. Regulatory Toxicology and Pharmacology 122: 104920.
            https://doi.org/10.1016/j.yrtph.2021.104920
            
           Santos,
            G.A., Angelo, T., Andrade, L.M., Silva, S.M.M., Magalhães, P.O., Cunha-Filho,
            M., Gelfuso, G.M., Taveira, S.F. & Gratieri, T. 2018. The role of
            formulation and follicular pathway in voriconazole cutaneous delivery from
            liposomes and nanostructured lipid carriers. Colloids and Surfaces B:
              Biointerfaces 170: 341-346. https://doi.org/10.1016/j.colsurfb.2018.06.037
            
           Santos,
            A.C., Pereira-Silva, M., Guerra, C., Costa, D., Peixoto, D., Pereira, I., Pita,
            I., Ribeiro, A.J. & Veiga, F. 2020. Topical minoxidil-Loaded nanotechnology
            strategies for alopecia. Cosmetics 7(2): 21.
            https://doi.org/10.3390/COSMETICS7020021
            
           Satheeshan,
            K.N., Seema, B.R. & Manjusha, M.A.V. 2020. Development and evaluation of
            VCO based herbal hair tonic. Journal of Pharmacognosy and Phytochemistry 9(2): 485-493.
            https://www.phytojournal.com/archives/2020/vol9issue3/PartH/9-3-5-112.pdf
            
           Souto,
            E. 2004. Development of a controlled release formulation based on SLN and NLC
            for topical clotrimazole delivery. International Journal of Pharmaceutics 278(1): 71-77. https://doi.org/10.1016/s0378-5173(04)00153-x
            
           Taghiabadi,
            E., Nilforoushzadeh, M.A. & Aghdami, N. 2020. Maintaining hair inductivity
            in human dermal papilla cells: A review of effective methods. Skin
              Pharmacology and Physiology 33(5): 280-292.
            https://doi.org/10.1159/000510152
            
           Tanaka,
            S., Saito, M. & Tabata, M. 1980. Bioassay of crude drugs for hair growth
            promoting activity in mice by a new simple method. Planta Medica 40(Suppl.): 84-90. https://doi.org/10.1055/s-2008-1075009
            
           Todo,
            H. & Mohd. F. 2017. Related topic: Drug permeation through hair follicles.
            In Skin Permeation and Disposition of Therapeutic and Cosmeceutical
              Compounds, edited by Sugibayashi, K. Tokyo: Springer. pp. 399-409.
            https://doi.org/10.1007/978-4-431-56526-0_36
            
           Toll,
            R., Jacobi, U., Richter, H., Lademann, J., Schaefer, H. & Blume-Peytavi, U.
            2004. Penetration profile of microspheres in follicular targeting of terminal
            hair follicles. Journal of Investigative Dermatology 123(1): 168-176.
            https://doi.org/10.1111/j.0022-202X.2004.22717.x
            
           Truong,
            V.L., Bak, M.J., Lee, C., Jun, M. & Jeong, W.S. 2017. Hair regenerative
            mechanisms of red ginseng oil and its major components in the
            testosterone-induced delay of anagen entry in C57BL/6 mice. Molecules 22(9): 1505. https://doi.org/10.3390/molecules22091505.
            
           Vanhoutte,
            P.M., Zhao, Y., Xu, A. & Leung, S.W.S. 2016. Thirty years of saying NO:
            Sources, fate, actions, and misfortunes of the endothelium-derived vasodilator
            mediator. Circulation Research 119(2): 375-396.
            https://doi.org/10.1161/CIRCRESAHA.116.306531.
            
           Vitorino,
            C., Sousa, J. & Pais, A. 2015. Overcoming the skin permeation barrier:
            Challenges and opportunities. Current Pharmaceutical Design 21(20):
            2698-2712. https://doi.org/10.2174/1381612821666150428124053.
            
           Wang,
            Z.D., Feng, Y., Sun, L., Gan, J., Li, X., Ding, W.F. & Chen, X.M. 2021.
            Anti-androgenetic alopecia effect of policosanol from chinese wax by regulating
            abnormal hormone levels to suppress premature hair follicle entry into the
            regression phase. Biomedicine and Pharmacotherapy 136: 111241.
            https://doi.org/10.1016/j.biopha.2021.111241
            
           Wang,
            Z.D., Feng, Y., Ma, L.Y., Li, X., Ding, W.F. & Chen, X.M. 2017. Hair growth
            promoting effect of white wax and policosanol from white wax on the mouse model
            of testosterone-induced hair loss. Biomedicine and Pharmacotherapy 89:
            438-446. https://doi.org/10.1016/j.biopha.2017.02.036
            
           Yazdani-Arazi,
            S.N., Ghanbarzadeh, S., Adibkia, K., Kouhsoltani, M. & Hamishehkar, H.
            2017. Histological evaluation of follicular delivery of arginine via
            nanostructured lipid carriers: A novel potential approach for the treatment of
            alopecia. Artificial Cells, Nanomedicine and Biotechnology 45(7):
            1379-1387. https://doi.org/10.1080/21691401.2016.1241794
            
           Yokouchi,
            M. & Kubo, A. 2018. Maintenance of tight junction barrier integrity in cell
            turnover and skin diseases 27(8): 876-883. Experimental Dermatology https://doi.org/10.1111/exd.13742
            
           Zhang,
            B., Zhang, R.W., Yin, X.Q., Lao, Z.Z., Zhang, Z., Wu, Q.G., Yu, L.W., Lai,
            X.P., Wan, Y.H. & Li, G. 2016. Inhibitory activities of some traditional
            Chinese herbs against testosterone 5α-reductase and effects of Cacumen
              platycladi on hair re-growth in testosterone-treated mice. Journal of
                Ethnopharmacology 177: 1-9. https://doi.org/10.1016/j.jep.2015.11.012.
            
           
            
            
               
             *Pengarang untuk
            surat-menyurat; email: nfkurniati@fa.itb.ac.id       
          
          
           
         
            
          
           
          
           
           |