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Enhanced permeability and pharmacokinetics of fattigated peptide drug in sublingual tablet

  • 박지민 (아주대학교 일반대학원)

초록/요약

The purpose of this research was to investigate in vitro and in vivo drug delivery performance of non-invasive sublingual tablet containing leuprolide (LEU)-oleic acid (OA) nanoparticles (LON) and deformable LON (d-LON) with or without adding permeation enhancers (PEs). d-LON was prepared via self-assembly of LEU- OA conjugate (LOC) while d-LON was prepared by incorporating α- phosphatidylcholine (PC) into LON. To further improve LEU permeability, various PEs such as lauroyl-L-carnitine (LLC), sodium decanoate (SD), salcaprozate sodium (SNAC), poloxamer 188 (P188), hydroxypropyl beta cyclodextrin (HPβCD), sodium lauryl sulfate (SLS), and sodium oleate (SO) were screened in the solution of different LEU types (LEU, LOC, LON, and d-LON) using Franz diffusion cell. PEs could readily increase the permeability in all LEU types. Most of all, d-LON adding LLC, SD, and SNAC demonstrated the highest permeability, giving 28.9, 33.0 and 34.4%, respectively. The sublingual tablets were designed to be thin and wide to give rapid disintegration, approximately within 2 min followed by immediate release within 10 min over 90% when contacting with saliva. The d-LON-loaded sublingual tablets adding LLC, SD and SNAC also demonstrated the enhanced permeabilities, giving 28.2 ± 0.81 % (F3), 31.7 ± 0.49 % (F4), 37.3 ± 0.76 % (F5) and respectively as compared to 20.9 ± 0.36 % (F2) in the absence of PEs. In pharmacokinetic studies conducted in beagle dogs, the LON-loaded sublingual tablet without adding PEs (F1) was unable to be delivered into systemic circulation so that no LEU was detected. In contrast, SD (F4) in d-LON-loaded sublingual tablets exhibited the highest bioavailability (AUClast: 1658.39 ± 1236.54 h·pg/mL) while AUClast of LLC (F3) and SNAC (F5) gave 938.76 ± 52.08 h·pg/mL and 31.50 ± 24.65 h·pg/mL, respectively. These findings suggested that d-LON-loaded sublingual tablet incorporating PEs were very crucial to deliver LEU via sublingual route. The current d-LON-loaded sublingual tablet could be also used to substitute the current LEU injectable for better patient-centric drug delivery.

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목차

1. Introduction 1
2. Materials and Methods 4
2.1. Materials 4
2.2. Preparation of LOC, LON and d-LON 4
2.3. HPLC analysis 5
2.4. Screening of permeation enhancers 5
2.5. Formulation and Preparation of LON or d-LON loaded sublingual tablets 8
2.6. Characterization of LON and d-LON 10
2.6.1. Dynamic light scattering (DLS) 10
2.6.2. Field-emission scanning electron microscopy (FE-SEM) 10
2.7. Evaluation of LON or d-LON loaded sublingual tablets 10
2.7.1. Weight, thickness and drug content 10
2.7.2. In vitro disintegration 11
2.7.3. Fourier-transform infrared spectroscopy (FT-IR) 11
2.7.4. Differential scanning calorimetry (DSC) 11
2.7.5. In vitro dissolution study 12
2.7.6. In vitro permeability 12
2.8. In vivo pharmacokinetics 12
2.8.1 Animal study 12
2.8.2 Drug administration 12
2.8.3 HPLC-MS/MS analysis 13
3. Results and discussions 14
3.1. Characterization of LON and d-LON 14
3.2. Screening of permeation enhancers 17
3.3. Evaluation of LON (F1) or d-LON (F2-F5)-loaded sublingual tablets 21
3.3.1. Morphology, surface and cross-section 21
3.3.2. Physicochemical properties 23
3.3.3. Fourier-transform infrared spectroscopy (FT-IR) 25
3.3.4. Differential scanning calorimetry (DSC) 26
3.3.5. In vitro disintegration study 29
3.3.6 In vitro dissolution study 31
3.3.7 In vitro permeability study 33
3.4. In vivo pharmacokinetic evaluation in beagle dogs 35
4. Conclusions 39
5. References 40
국문초록 44

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