Tổng hợp hydroxyalkyl β cyclodextrin ứng dụng làm tá dược tăng độ tan trong bào chế thuốc

i BỘ GIÁO DỤC VÀ ĐÀO TẠO BỘ Y TẾ ĐẠI HỌC Y DƯỢC THÀNH PHỐ HỒ CHÍ MINH PHÙNG ĐỨC TRUYỀN TỔNG HỢP HYDROXYALKYL-β-CYCLODEXTRIN ỨNG DỤNG LÀM TÁ DƯỢC TĂNG ĐỘ TAN TRONG BÀO CHẾ THUỐC Chuyên ngành: Công nghệ dược phẩm Mã số: 62730101 LUẬN ÁN TIẾN SĨ DƯỢC HỌC Người hướng dẫn khoa học: PGS.TS Đặng Văn Tịnh PGS.TS Huỳnh Văn Hóa TP Hồ Chí Minh - Năm 2014 ii LỜI CAM ĐOAN Tôi cam đoan cơng trình nghiên cứu tơi Các số liệu, kết nêu luận án trung thực chưa công bố cơng trình khác Phùng Đức Truyền MỤC LỤC Trang phụ bìa Trang Lời cam đoan MỤC LỤC iii DANH MỤC CÁC KÝ HIỆU, CÁC CHỮ VIẾT TẮT vi DANH MỤC CÁC BẢNG ix DANH MỤC CÁC HÌNH xiii DANH MỤC CÁC BIỂU ĐỒ xiv DANH MỤC CÁC SƠ ĐỒ xvi ĐẶT VẤN ĐỀ CHƯƠNG TỔNG QUAN TÀI LIỆU 1.1 Tổng hợp 2-hydroxypropyl-β-cyclodextrin (HPβCD) 1.2 Tổng hợp 2-hydroxybutyl-β-cyclodextrin (HBβCD) 13 1.3 Tối ưu hóa thông số phản ứng tổng hợp 14 1.4 Phức thuốc-hydroxypropyl-β-cyclodextrin (thuốc-HPβCD) 15 1.5 Phức thuốc-hydroxybutyl-β-cyclodextrin (thuốc-HBβCD) 25 1.6 Các hoạt chất ứng dụng để tạo phức với 2-hydroxypropyl-βcyclodextrin 2-hydroxybutyl-β-cyclodextrin 26 CHƯƠNG - ĐỐI TƯỢNG VÀ PHƯƠNG PHÁP NGHIÊN CỨU 31 2.1 Đối tượng, hóa chất, dung mơi, nguyên liệu, trang thiết bị 31 2.1.1 Đối tượng nghiên cứu 31 2.1.2 Hóa chất, dung môi, nguyên liệu, máy, thiết bị dùng cho tổng hợp, điều chế 31 2.1.3 Tối ưu hóa qui trình tổng hợp xử lý thống kê với trợ giúp phần mềm: 33 2.2 Phương pháp nghiên cứu 33 2.2.1 Tổng hợp 2-hydroxypropyl-β-cyclodextrin (HPβCD) 33 2.2.2 Tổng hợp 2-hydroxybutyl-β-cyclodextrin (HBβCD) 40 2.2.3 Điều chế phức rutn-hydroxypropyl-β-cyclodextrin (R-HPβCD) 42 2.2.4 Điều chế phức rutn-hydroxybutyl-β-cyclodextrin (R-HBβCD) 46 2.2.5 So sánh độ hòa tan, độ tan rutn phức R-HBβCD rutn phức R-HPβCD 47 2.2.6 Điều chế phức itraconazol-hydroxypropyl-β-cyclodextrin (ITZ-HPβCD) 47 2.2.7 Điều chế phức itraconazol-hydroxybutyl-β-cyclodextrin (ITZ-HBβCD) 49 2.2.8 So sánh độ hòa tan, độ tan itz phức ITZ-HBβCD itz phức ITZ-HPβCD 50 2.2.9 Điều chế phức meloxicam-hydroxypropyl-β-cyclodextrin (ME-HPβCD) 50 CHƯƠNG KẾT QUẢ NGHIÊN CỨU 53 3.1 Tổng hợp 2-hydroxypropyl-β-cyclodextrin (HPβCD) 53 3.2 Tổng hợp 2-hydroxybutyl-β-cyclodextrin (HBβCD) 65 3.3 Điều chế phức rutin-hydroxypropyl-β-cyclodextrin (R-HPβCD) 75 3.4 Điều chế phức rutin-hydroxybutyl-β-cyclodextrin (R-HBβCD) 82 3.5 So sánh độ hòa tan, độ tan rutn phức R-HBβCD rutn phức R-HPβCD 86 3.6 Điều chế phức itraconazol-hydroxypropyl-β-cyclodextrin (ITZ-HPβCD) 88 3.7 Điều chế phức itraconazol-hydroxybutyl-β-cyclodextrin (ITZ-HBβCD) 93 3.8 So sánh độ hòa tan, độ tan itz phức ITZ-HBβCD itz phức ITZ-HPβCD 98 3.9 Điều chế phức meloxicam-hydroxypropyl-β-cyclodextrin (ME-HPβCD) 100 CHƯƠNG BÀN LUẬN 106 4.1 Tổng hợp 2-hydroxypropyl-β-cyclodextrin 106 4.2 Tổng hợp 2-hydroxybutyl-β-cyclodextrin 120 4.3 Điều chế phức R-HPβCD 124 4.4 Điều chế phức R-HBβCD 150 4.5 So sánh độ hòa tan, độ tan rutn phức R-HBβCD rutn phức R-HPβCD 151 4.6 Điều chế phức ITZ-HPβCD 151 4.7 Điều chế phức ITZ-HBβCD 156 4.8 So sánh độ hòa tan, độ tan itz phức ITZ-HBβCD itz phức ITZ-HPβCD 132 4.9 Điều chế phức ME-HPβCD 132 KẾT LUẬN 161 KIẾN NGHỊ 162 DANH MỤC CÁC CƠNG TRÌNH NGHIÊN CỨU ĐÃ CÔNG BỐ TÀI LIỆU THAM KHẢO PHỤ LỤC DANH MỤC CÁC KÝ HIỆU, CÁC CHỮ VIẾT TẮT Ký hiệu, từ viết tắt Chữ đầy đủ nghĩa tiếng Việt AUC Area Under the Curve (Diện tích đường cong) BP Britsh Pharmacopoeia (Dược điển Anh) CE Complexation Eficiency (Hiệu tạo phức) Cmax Nồng độ tối đa COSY Correlaton Spectroscopy: (Phổ COSY) d Doublet (Mũi đôi) dd Doublet of doublets (Mũi đôi-đôi) DĐVN Dược điển Việt nam DEPT Distortonless Enhancement by Polarizaton Transfer (Phổ DEPT) dm Dung môi DMF Dimethylformamid DMSO Dimethylsulfoxyd DS Degree of Substtuton (Độ thế) DSC Differental Scanning Calorimetry (Phân tích nhiệt vi sai) Eur Ph European Pharmacopoeia (Dược điển Châu Âu) HBβCD 2-hydroxybutyl-β-cyclodextrin HMBC Heteronuclear Multiple Bond Coherence (Phổ HMBC) HPLC High Performance Liquid Chromatography (Sắc ký lỏng hiệu cao) HPβCD 2-hydroxypropyl-β-cyclodextrin HSQC Heteronuclear Single Quantum Correlaton (Phổ HSQC) IR Infrared (Hồng ngoại) Itz Itraconazol vii ITZ-HBβCD HPβCD Phức itraconazol-hydroxybutyl-β-cyclodextrin ITZPhức itraconazol-hydroxypropyl-β-cyclodextrin J Hằng số ghép K1:1 Hằng số cân (Hằng số bền phức chất) kDa Kilodalton (Đơn vị đo khối lượng phân tử) kl/tt Khối lượng/thể tích m Multplet (Mũi đa) ME Meloxicam m/z Tỷ lệ khối lượng điện tích ion ME-HPβCD Phức meloxicam-hydroxypropyl-β-cyclodextrin MS Mass Spectroscopy (Phổ khối) ms Molar substtuton (Mức độ thay phân tử) NMR Nuclear Magnetc Resonance (Cộng hưởng từ hạt nhân) NOESY Nuclear Overhauser Enhancement Spectroscopy (Phổ NOESY) pic Đỉnh, (Mũi) ppm Part per million (Phần triệu) R-HBβCD Phức rutn-hydroxybutyl-β-cyclodextrin R-HPβCD Phức rutn-hydroxypropyl-β-cyclodextrin ROESY Rotatng-Frame Overhauser Enhancement Spectroscopy (Phổ ROESY) RSD Relatve Standard Deviaton (Độ lệch chuẩn tương đối) s Singlet (Mũi đơn) SD Standard Deviaton (Độ lệch chuẩn) SEM Scanning Electron Microscope (Kính hiển vi điện tử quét) t Triplets (Mũi ba) TCCS Tiêu chuẩn sở TCNSX Tiêu chuẩn nhà sản xuất TLC Thin Layer Chromatography (Sắc ký lớp mỏng) Tmax Thời gian đạt nồng độ tối đa TT Thuốc Thử tt Thể tích USP-NF The United States Pharmacopoeia and The Natonal Formulary (Dược điển Dược thư Hoa kỳ) UV Ultraviolet (Tử ngoại) X Giá trị trung bình βCD Beta Cyclodextrin DANH MỤC CÁC BẢNG Trang Bảng 2.1 Danh mục nguyên liệu hóa chất dùng cho tổng hợp 31 Bảng 2.2 Danh mục nguyên liệu dùng cho điều chế phức 31 Bảng 2.3 Danh mục hóa chất dùng cho phân tích, kiểm nghiệm 32 Bảng 2.4 Danh mục máy, thiết bị 32 Bảng 3.1 Ảnh hưởng nồng độ NaOH đến hiệu suất DS phản ứng tổng hợp HPβCD 54 Bảng 3.2 So sánh phổ IR HPβCD tổng hợp HPβCD thương mại 54 13 Bảng 3.3 So sánh độ dịch chuyển hóa học phổ H C-NMR HPβCD tổng hợp HPβCD thương mại 55 Bảng 3.4 Ảnh hưởng vận tốc khuấy đến hiệu suất DS phản ứng tổng hợp HPβCD 56 Bảng 3.5 Ảnh hưởng nhiệt độ đến hiệu suất DS phản ứng tổng hợp HPβCD 56 Bảng 3.6 Ảnh hưởng thời gian đến hiệu suất DS phản ứng tổng hợp HPβCD 57 Bảng 3.7 Mã hóa yếu tố biến thiên khảo sát qui trình tổng hợp HPβCD 58 Bảng 3.8 Bố trí thí nghiệm Box-Behnken mức kiểu bề mặt đáp ứng kết hiệu suất DS qui trình tổng hợp HPβCD 59 Bảng 3.9 Hiệu suất DS phản ứng tổng hợp HPβCD điều kiện tối ưu 60 Bảng 3.10 Sản phẩm phản ứng tổng hợp HPβCD với tỷ lệ mol βCD : 1,2-propylen oxid khác 61 Bảng 3.11 Hiệu suất DS phản ứng tổng hợp HPβCD cỡ lô kg 62 Bảng 3.12 Kết kiểm nghiệm HPβCD tổng hợp 63 Bảng 3.13 Độ ổn định HPβCD tổng hợp 64 Bảng 3.14 Công thức (cho lô) tổng hợp HPβCD 64 screening tool for estimating the potental of 2-hydroxypropyl-β-cyclodextrin complexation for solubilizaton purposes”, International Journal of Pharmaceutics 295, pp.163-175 12 Aiju Chen, Min Liu, Lina Dong, Dezhi Sun (2013), “Study on the effect of solvent on the inclusion interacton of hydroxypropyl-β-cyclodextrin with three kinds of coumarins by phase solubility method”, Fluid 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(βCD) nghiên cứu rộng rãi để tạo phức làm tăng độ tan dược chất [63] Tuy nhiên độ tan βCD thấp có độc tính thận nên khả ứng dụng βCD bị giới hạn [17], [84] Các dẫn xuất hydroxyalkyl βCD có độ. .. sản phẩm phản ứng tổng hợp lên cỡ lô kg 1.3 Xây dựng têu chuẩn sở sản phẩm tổng hợp đạt yêu cầu làm tá dược Ứng dụng 2-hydroxypropyl -β- cyclodextrin 2-hydroxybutyl -β- cyclodextrin tổng hợp vào tạo