Formulation design and improved physicochemical properties of mucoadhesive buccal film containing peptide-fatty acid conjugate and nanoparticles
- 주제(키워드) Solvent casting , Mucoadhesive buccal film , Leuprolide-oleic acid conjugate , Leuprolide-oleic acid nanoparticle , Deformable nanoparticle , Fattigaiton-platform
- 주제(DDC) 615.1
- 발행기관 아주대학교
- 지도교수 이범진
- 발행년도 2023
- 학위수여년월 2023. 8
- 학위명 석사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000032929
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
The objective of this study is to manufacture mucoadhesive buccal films of leuprolide (LEU) with improved mucosal permeability. To improve mucosal permeability, LEU-oleic acid conjugate (LOC) and LEU-oleic acid nanoparticles (LON) were used, which were developed in our previous study. In addition, deformable LON (d-LON) was developed in this study by adding l-α-phosphatidylcholine to LON as an edge activator. The particle size, zeta potential, and deformability index (DI) of LON and d-LON were evaluated, and in the case of DI, d-LON had a higher value of about 5.73 times that of LON. The films were prepared by solvent casting method using various ratios of Eudragit RLPO and Hydroxypropyl methylcellulose (HPMC K4M) with propylene glycol as a plasticizer. The formulations were optimized by physicochemical properties, in vitro residence time, in vitro dissolution (US Pharmacopeia paddle II method), and in vitro permeability (Franz diffusion cell, DHC-6TD, Logan, USA), and the dose of the buccal film was also set according to the results of dissolution, and permeation test. The selected formulation (F2) had the appropriate physicochemical properties and showed the highest dissolution rate (97.31 ± 8.61%) and permeability (21.73 ± 1.28%) for 6 hours. Finally, LEU (1 mg) and equivalent LEU doses of LOC, LON, and d-LON-loaded buccal films were prepared and compared. The d-LON-loaded buccal films showed the highest permeability (51.38 ± 1.64%) for 6 hours which was 2.36 times higher than LEU-loaded buccal films. These results suggest that buccal films containing d-LON can increase patient compliance by improving the bioavailability and permeability of LEU, by replacing the administration route in which only the parenteral route existed.
more초록/요약
본 연구의 목적은 개선된 점막 투과성을 갖는 류프롤라이드의 점막 접착성 박칼필름을 설계하는 것이다. 점막 투과성을 향상시키기 위해 이전 연구에서 개발된 류프롤라이드-올레산 접합체 (LOC)와 자가 조립 류프롤라이드-올레산 나노입자 (LON)를 사용했다. 또한 본 연구에서는 LON에 l-α-포스파티딜콜린을 첨가하여 변형 가능한 LON(d-LON)을 개발하였다. LON과 d-LON의 입도, 제타전위 및 변형률(DI)을 평가하였으며, 변형률의 경우 LON의 약 5.73배의 값을 나타내었다. 상기 필름들은 가소제로서 프로필렌글리콜과 함께 Eudragit RLPO와 Hydroxypropyl methylcellulose (HPMC K4M)을 다양한 비율로 혼합하여 용매 캐스팅 방법에 의해 제조되었다. 제형은 물리화학적 특성, in vitro 체류시간, in vitro 용출시험 (US Pharmacopeia pad II method), in vitro 투과성 (Franz diffusion cell, DHCP-6TD, Logan, USA)에 의해 최적화되었으며, 박칼필름의 투여량도 용출시험 및 투과도 결과에 따라 설정하였다. 선택된 제제는 적절한 물리화학적 특성을 가지며 6시간 동안 가장 높은 용출률 (97.31 ± 8.61%)과 투과율 (13.87 ± 1.36%)을 보였다. 마지막으로 류프롤라이드 기준으로 1mg 용량을 탑재한 LOC, LON 및 d-LON 준비하여 비교하였다. d-LON이 로딩된 박칼필름은 6시간 동안 류프롤라이드 박칼필름보다 2.36배 높은 투과율 (51.38±1.64%)을 보였다. 이러한 결과는 d-LON을 포함하는 박칼필름이 비경구 경로만 존재했던 투여 경로를 대체함으로써 류프롤라이드의 생물학적 가용성과 투과성을 향상시킴으로써 환자 친화도를 증가시킬 수 있음을 시사한다.
more목차
1. Introduction 1
2. Materials and Methods 5
2.1. Materials 5
2.2. Preparation of mucoadhesive buccal films 5
2.2.1. Preparation of LOC, LON, and d-LON 5
2.2.2. Preparation of mucoadhesive buccal films 6
2.3. Physicochemical characterizations of LON and d-LON 9
2.3.1. Dynamic light scattering (DLS) 9
2.3.2. Deformability index 9
2.4. Characterizations of mucoadhesive buccal films 9
2.4.1. Weight and thickness variations 9
2.4.2. Drug content 10
2.4.3. Folding endurance 10
2.4.4. Surface pH 10
2.4.5. Swelling study 10
2.4.6. Field Emission Scanning Electron Microscopy (FE-SEM) 11
2.4.7. Fourier transform-infrared (FT-IR) spectrometer 11
2.4.8. Differential Scanning Calorimetry (DSC) 11
2.4.9. In vitro residence time 12
2.4.10. In vitro dissolution study 12
2.4.11. In vitro permeability 12
2.4.12. HPLC analysis 13
3. Results and discussions 15
3.1. Physicochemical characterization of LON and d-LON 15
3.2. Formulation optimization of mucoadhesive buccal films 17
3.2.1. Physical properties of mucoadhesive buccal films 17
3.2.2. Swelling study and In vitro residence time 19
3.2.3. In vitro dissolution study of formulations 22
3.2.4. In vitro permeability of formulations 24
3.3. Optimized mucoadhesive buccal films characterization 26
3.3.1. Field Emission Scanning Electron Microscopy (FE-SEM) 26
3.3.2. Fourier transform-infrared (FT-IR) spectrometer 28
3.3.3. Differential Scanning Calorimetry (DSC) 30
3.3.4. In vitro dissolution study 32
3.3.5. In vitro permeability 34
4. Conclusions 36
5. References 38
국문초록 43
