In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals

We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50–150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5–10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.

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In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats

Cells ◽

10.3390/cells9102171 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2171

Author(s):

Saori Deguchi ◽

Fumihiko Ogata ◽

Mizuki Yamaguchi ◽

Misa Minami ◽

Hiroko Otake ◽

...

Keyword(s):

Therapeutic Approaches ◽

In Situ Gel ◽

Retinal Dysfunction ◽

Atp Production ◽

Oletf Rats ◽

Bead Mill ◽

Long Evans ◽

The Right ◽

In Situ Gelling

We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.

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Injectable in situ gelling delivery system for the treatment of jawbone infections

Therapeutic Delivery ◽

10.4155/tde-2021-0054 ◽

2021 ◽

Author(s):

Shreshtha Dash ◽

Somnath Singh ◽

Alekha K Dash

Keyword(s):

Lactic Acid ◽

Sustained Release ◽

Cell Viability ◽

Yield Stress ◽

Delivery System ◽

Pluronic F127 ◽

Sustained Delivery ◽

In Situ Gelling ◽

Sustained Rate

Aim: A polymeric in situ gelling delivery system for localized and sustained delivery to jawbone infections was developed. Materials & methods: In situ gelling delivery systems were prepared using either poly-dl-lactic acid or chitosan and Pluronic F127/Pluronic F68. Metronidazole nanoparticles were prepared using poly (dl-lactide-co-glycolide) or chitosan. Poly (dl-lactide-co-glycolide) was used for microparticles. Particles were characterized for size, charge and morphology. Results: Viscosity and yield stress of the gels were 0.4 Pa.s and 2 Pa, respectively, with 70% cell viability over 72 h. Around 90% of loaded metronidazole was released at a sustained rate over 1 week. Conclusion: Use of appropriate amount of nano/microparticles in the gel resulted in a sustained release over a period of 1 week – needed for jawbone infection.

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Balance of Drug Residence and Diffusion in Lacrimal Fluid Determine Ocular Bioavailability in In Situ Gels Incorporating Tranilast Nanoparticles

Pharmaceutics ◽

10.3390/pharmaceutics13091425 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1425

Author(s):

Misa Minami ◽

Hiroko Otake ◽

Yosuke Nakazawa ◽

Norio Okamoto ◽

Naoki Yamamoto ◽

...

Keyword(s):

Residence Time ◽

Pluronic F127 ◽

Lacrimal Fluid ◽

Significant Difference ◽

Bead Mill ◽

Conjunctival Inflammation ◽

Ocular Bioavailability ◽

Factor Α ◽

And Diffusion

We previously designed ophthalmic formulations (nTRA) containing tranilast nanoparticles (Tra-NPs) with high uptake into ocular tissues. In this study, we used in situ gel (ISG) bases comprising combinations of pluronic F127 (F127) and methylcellulose (MC/F127), pluronic F68 (F68/F127), and Carbopol (Car/F127), and we developed in situ gels incorporating Tra-NPs (Tra-NP-incorporated ISNGs) such as nTRA-F127, nTRA-MC/F127, nTRA-F68/F127, and nTRA-Car/F127. Moreover, we demonstrated the therapeutic effect on conjunctival inflammation using lipopolysaccharide-induced rats. Each Tra-NP-incorporated ISNG was prepared by the bead mill method, the particle size was 40–190 nm, and the tranilast release and diffusion from formulation were nTRA > nTRA-F127 > nTRA-F68/F127 > nTRA-Car/F127 > nTRA-MC/F127. In the Tra-NP-incorporated ISNGs, the tranilast residence time in the lacrimal fluid, cornea, and conjunctiva was prolonged, although the Cmax was attenuated in comparison with nTRA. On the other hand, no significant difference in conjunctival inflammation between non- and nTRA-F127-instilled rats was found; however, the nTRA-F68/F127, nTRA-Car/F127, and nTRA-MC/F127 (combination-ISG) attenuated the vessel leakage, nitric oxide, and tumor necrosis factor-α expression. In particular, nTRA-F68/F127 was significant in preventing the conjunctival inflammation. In conclusion, we found that the combination-ISG base prolonged the residence time of Tra-NPs; however, Tra-NP release from the formulation was attenuated, and the Tmax was delayed longer than that in nTRA. The balance of drug residence and diffusion in lacrimal fluid may be important in providing high ocular bioavailability in formulations containing solid nanoparticles.

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THERMOREVERSIBLE, MUCOADHESIVE IN SITU GELLING FORMULATIONS FOR NASAL DELIVERY OF PROPRANOLOL HYDROCHLORIDE

INDIAN DRUGS ◽

10.53879/id.50.09.p0041 ◽

2013 ◽

Vol 50 (09) ◽

pp. 41-51

Author(s):

R Bhat ◽

◽

Z. Abbas ◽

N.G.N. Swamy

Keyword(s):

Nasal Delivery ◽

Propranolol Hydrochloride ◽

Gelation Temperature ◽

Enhanced Absorption ◽

Diffusion Controlled ◽

Thixotropic Behaviour ◽

In Situ Gelling ◽

Carbopol 934P

Mucoadhesive, thermoreversible propranolol hydrochloride formulations were made to overcome firstpass metabolism, to prolong the drug residence time in the nasal cavity and to improve the therapeutic efficacy. In situ gelling formulations were prepared by cold technique using Pluronic F-127, Pluronic F-68 / Polyvinyl Alcohol complex and Carbopol 934P as the mucoadhesive polymer. Formulations were so modulated as to have gelation temperature below 340C to ensure gelation at the physiological temperature after intranasal administration. Gelation was characterized by physical appearance as well as by rheological evaluation. The gelation temperature decreased with increase in Carbopol concentration, whereas mucoadhesive force increased. The formulations displayed a thixotropic behaviour. The pH of the nasal gels was found to be in the range of 5.3 to 5.6 very much ideal for nasal delivery. The results of in vitro drug diffusion studies across the sheep nasal mucosa indicated that the drug release increased with increase in Carbopol concentration. The release was found to be matrix diffusion controlled and occurred by Fickian mechanism. It could be concluded that, the mucoadhesive, in situ gelling formulations of propranolol hydrochloride proved to be physically stable, convenient, effective nasal delivery systems ensuring prolonged nasal residence and assuring enhanced absorption.

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In situ gelling systems based on Pluronic F127/Pluronic F68 formulations for ocular drug delivery

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2016.02.027 ◽

2016 ◽

Vol 502 (1-2) ◽

pp. 70-79 ◽

Cited By ~ 91

Author(s):

Kosai Al Khateb ◽

Elvira K. Ozhmukhametova ◽

Marat N. Mussin ◽

Serzhan K. Seilkhanov ◽

Tolebai K. Rakhypbekov ◽

...

Keyword(s):

Drug Delivery ◽

Ocular Drug Delivery ◽

Pluronic F127 ◽

Pluronic F68 ◽

In Situ Gelling

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Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles

International Journal of Molecular Sciences ◽

10.3390/ijms19072138 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2138 ◽

Cited By ~ 9

Author(s):

Noriaki Nagai ◽

Fumihiko Ogata ◽

Miyu Ishii ◽

Yuya Fukuoka ◽

Hiroko Otake ◽

...

Keyword(s):

Skin Penetration ◽

Cytochalasin D ◽

Significant Information ◽

Bead Mill ◽

Penetration Mechanism ◽

Auc Value ◽

The Mean ◽

Transdermal Penetration ◽

Energy Dependent ◽

Transdermal Formulation

We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.

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Curcumin In Situ Gelling Polymeric Insert with Enhanced Ocular Performance

Pharmaceutics ◽

10.3390/pharmaceutics12121158 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1158

Author(s):

Hamdy Abdelkader ◽

David Wertheim ◽

Barbara Pierscionek ◽

Raid G. Alany

Keyword(s):

Ocular Surface ◽

Water Solubility ◽

Molecular Form ◽

Antioxidant Properties ◽

In Vitro Release ◽

Duration Of Action ◽

Corneal Permeability ◽

In Situ Gelling

The search for an ocular drug delivery system that could provide long-acting effects without a detriment to the anatomy and physiology of the eye remains a challenge. Polyphenolic compounds (curcumin in particular) have recently gained popularity due to their powerful antioxidant properties; yet curcumin suffers poor stability and water solubility. A conventional eye drop formulation of curcumin in the form of a suspension is likely to suffer a short duration of action requiring multiple instillations. On the other hand, polymeric in-situ gelling inserts offer the prospect of overcoming these limitations. The aim of this study was to prepare, characterize and evaluate in vivo, polymeric, in-situ gelling and mucoadhesive inserts for ocular surface delivery of curcumin. Different types and ratios of biocompatible polymers (HPMC, CMC, PL 127 and PVA) and three plasticizers along with the solvent casting method were adopted to prepare curcumin inserts. The inserts were investigated for their physicochemical characteristics, applicability, and suitability of use for potential placement on the ocular surface. The prepared inserts revealed that curcumin was mainly dispersed in the molecular form. Insert surfaces remained smooth and uniform without cracks appearing during preparation and thereafter. Improved mechanical and mucoadhesive properties, enhanced in vitro release (7.5- to 9-fold increases in RRT300 min) and transcorneal permeation (5.4- to 8.86-fold increases in Papp) of curcumin was achieved by selected in-situ gelling inserts compared to a control curcumin suspension. The developed inserts demonstrated acceptable ocular tolerability, enhanced corneal permeability, and sustained release of curcumin along with retention of insert formulation F7 on the ocular surface for at least two-hours. This insert provides a viable alternative to conventional eye drop formulations of curcumin.

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Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig

International Journal of Molecular Sciences ◽

10.3390/ijms22105137 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5137

Author(s):

Hiroko Otake ◽

Mizuki Yamaguchi ◽

Fumihiko Ogata ◽

Saori Deguchi ◽

Naoki Yamamoto ◽

...

Keyword(s):

Skin Penetration ◽

The Other ◽

Skin Tissue ◽

Significant Information ◽

Detailed Mechanism ◽

Carbopol Gel ◽

Göttingen Minipig ◽

Bead Mill ◽

Transdermal Penetration ◽

Energy Dependent

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79–216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs’ skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.

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Luliconazole-Loaded Thermosensitive Hydrogel as Aqueous based Nail Lacquer for the Treatment of Onychomycosis

Drug Delivery Letters ◽

10.2174/2210303109666190520081552 ◽

2019 ◽

Vol 9 (4) ◽

pp. 321-329

Author(s):

Rupinder K. Dhamoon ◽

Ramesh K. Goyal ◽

Harvinder Popli ◽

Madhu Gupta

Keyword(s):

Release Kinetics ◽

Pluronic F127 ◽

Current Therapy ◽

Thermosensitive Hydrogel ◽

Drying Time ◽

Nail Diseases ◽

Nail Lacquer ◽

In Situ Gelling

Background: Onychomycosis is a nail fungal infection which accounts for 50% of the nail diseases and is characterized by disfigurement and discoloration of nails. The current therapy includes oral and topical formulations both of which come with their own drawbacks. This has left a room for developing patient- compliant novel strategies which can facilitate drug delivery deeper into the nails effectively. Objective: The main objective of the present work was to develop and evaluate in situ gelling thermosensitive hydrogel as an aqueous nail lacquer for the treatment of onychomycosis. The idea was to enhance permeation of Luliconazole into the nail while simultaneously solubilizing it in a hydrophilic formulation. Methods: The sample of Luliconazole was authenticated using modern analytical techniques. The hydrogel- nail lacquer was prepared using poloxamer Pluronic F127. The formulation was evaluated in terms of drying time, viscosity, non- volatile content, pH, transition temperature, etc. In vitro study was done to check the drug release while determining release kinetics. In vitro transungual permeation study was done to check drug permeation through porcine hoof membrane. Stability studies were conducted to ensure formulation stability. Results: The results confirmed a stable formulation with enhanced permeation through porcine hoof membrane. Conclusion: The results support the potential use of in situ gelling thermo-sensitive hydrogels as a novel transungual formulation in the treatment of onychomycosis with a slight improvement in water resistance.

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