title: Novel dual-reverse thermosensitive solid lipid nanoparticle-loaded hydrogel for rectal administration of flurbiprofen with improved bioavailability and reduced initial burst effect.
abstract: The purpose of this study was to develop novel solid lipid nanoparticle (SLN)-loaded dual-reverse thermosensitive hydrogel (DRTH) for rectal administration of flurbiprofen with improved bioavailability and reduced initial burst effect. The flurbiprofen-loaded SLNs were prepared by hot homogenisation technique, after optimising the amounts of lipid mixture (tricaprin and triethanolamine in 8:2 weight ratio), drug and surfactant. The flurbiprofen-loaded thermosensitive SLN composed of drug, lipid mixture and surfactant at a weight ratio of 10/15/1.3 was a solid at room temperature, and changed to liquid form at physiological temperature due to its melting point of about 32°C. This SLN gave the mean particle size of about 190nm and entrapment efficiency of around 90%. The DRTHs were prepared by adding this flurbiprofen-loaded thermosensitive SLN in various poloxamer solutions. Their rheological characterisation, release and stability were investigated while a morphological and pharmacokinetic study was performed after its rectal administration to rats compared with the drug and hydrogel. Poloxamer 188 and SLN decreased the gelation temperature and gelation time, but increased the viscosity at 25°C, gel strength and mucoadhesive force of DRTHs. In particular, the DRTH composed of [SLN/P 407/P 188 (10%/15%/25%)] with the gelation temperature of about 35°C existed as liquid at room temperature, but gelled at 30-36°C, leading to opposite reversible property of SLN. Thus, it was easy to administer rectally, and it gelled rapidly inside the body. This DRTH gave a significantly increased dissolution rate of the drug as compared to the flurbiprofen, but significantly retarded as compared to the hydrogel, including the initial dissolution rate. Moreover, this DRTH gave significantly higher plasma concentration and 7.5-fold AUC values compared to the drug, and lower initial plasma concentration and Cmax value compared to the hydrogel due to reduced initial burst effect. No damage in rectal mucosa was observed after the application of DRTH. Thus, this DRTH system with improved bioavailability and reduced initial burst effect would be recommended as an alternative for the flurbiprofen-loaded rectal pharmaceutical products.
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
authors.forename: Fakhar Ud
authors.initials: FU
authors.lastname: Din
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
authors.forename: Omer
authors.initials: O
authors.lastname: Mustapha
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
authors.forename: Dong Wuk
authors.initials: DW
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
authors.forename: Rehmana
authors.initials: R
authors.lastname: Rashid
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
authors.forename: Jong Hyuck
authors.initials: JH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749, South Korea.
authors.forename: Ju Yeon
authors.initials: JY
authors.lastname: Choi
authors.affiliation: College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, South Korea.
authors.forename: Sae Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749, South Korea.
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749, South Korea. Electronic address: jongohkim@yu.ac.kr.
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea. Electronic address: hangon@hanyang.ac.kr.
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
mesh_terms: D000268:Adhesiveness; D000285:Administration, Rectal; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004983:Ethanolamines / Q000737:chemistry*; D005480:Flurbiprofen / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D006358:Hot Temperature; D020100:Hydrogels; D008297:Male; D050997:Nanomedicine; D053758:Nanoparticles; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012212:Rheology; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D014280:Triglycerides / Q000737:chemistry*; D014783:Viscosity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D004983:Ethanolamines; D020100:Hydrogels; D013501:Surface-Active Agents; D014280:Triglycerides; D020442:Poloxamer; D005480:Flurbiprofen; C009546:triethanolamine; C010800:tricaprin
keywords: Bioavailability; Burst effect; Dual-reverse thermosensitive hydrogel; Flurbiprofen; Solid lipid nanoparticle