scholarly journals Dry Tablet Formulation of PLGA Nanoparticles with a Preocular Applicator for Topical Drug Delivery to the Eye

Pharmaceutics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 651 ◽  
Author(s):  
Woo Mi Ryu ◽  
Se-Na Kim ◽  
Chang Hee Min ◽  
Young Bin Choy
Keyword(s):  
Fold Increase ◽  
Topical Administration ◽  
Plga Nanoparticles ◽  
Drug Dose ◽  
Eye Drops ◽  
Drug Bioavailability ◽  
Sustained Drug Release ◽  
Accurate Dose ◽  
Viscosity Enhancement

To enhance ocular drug bioavailability, a rapidly dissolving dry tablet containing alginate and drug-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles was proposed. For hygienic and easy administration of an accurate drug-dose with this tablet, the use of a preocular applicator was suggested. Herein, a dry tablet was prepared by embedding dexamethasone-loaded PLGA nanoparticles in alginate, which was deposited on the tip of the applicator. The nanoparticles were loaded with 85.45 μg/mg drug and exhibited sustained drug release for 10 h. To evaluate in vivo efficacy, dexamethasone concentration in the aqueous humor was measured after topical administration of the dry tablet, with the applicator, to rabbit eyes and was compared to that achieved with Maxidex®, a commercially-available dexamethasone eye drops. When applied with the preocular applicator, the dry tablet containing alginate could be fully detached and delivered to the eye surface. In fact, it showed up to 2 h of nanoparticle retention on the preocular surface due to tear viscosity enhancement, causing an estimated 2.6-fold increase in ocular drug bioavailability compared to Maxidex®. Therefore, the preocular applicator combined with a dry alginate tablet containing PLGA nanoparticles can be a promising system for aseptically delivering an accurate dose of ophthalmic drug with enhanced bioavailability.

scholarly journals New Insights into the Mechanisms of Action of Topical Administration of GLP-1 in an Experimental Model of Diabetic Retinopathy

2019 ◽  
Vol 8 (3) ◽  
pp. 339 ◽  
Author(s):  
Joel Sampedro ◽  
Patricia Bogdanov ◽  
Hugo Ramos ◽  
Cristina Solà-Adell ◽  
Mireia Turch ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Neurovascular Unit ◽  
Topical Administration ◽  
Inflammatory Factors ◽  
Eye Drops ◽  
Beneficial Effects ◽  
Apoptotic Protein ◽  
Glucagon Like Peptide 1 ◽  
Underlying Mechanisms

The main goals of this work were to assess whether the topical administration of glucagon-like peptide-1 (GLP-1) could revert the impairment of the neurovascular unit induced by long-term diabetes (24 weeks) in diabetic mice and to look into the underlying mechanisms. For that reason, db/db mice were treated with eye drops of GLP-1 or vehicle for 3 weeks. Moreover, db/+ mice were used as control. Studies performed in vivo included electroretinogramand the assessment of vascular leakage by using Evans Blue. NF-κB, GFAP and Ki67 proteins were analyzed by immunofluorescence (IF). Additionally, caspase 9, AMPK, IKBα, NF-κB, AKT, GSK3, β-catenin, Bcl-xl, and VEGF were analyzed by WB. Finally, VEGF, IL-1β, IL-6, TNF-α, IL-18, and NLRP3 were studied by reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. We found that topical administration of GLP-1 reverted reactive gliosis and albumin extravasation, and protected against apoptosis and retinal dysfunction. Regarding the involved mechanisms, GLP-1 exerted an anti-inflammatory action by decreasing NF-κB, inflammosome, and pro-inflammatory factors. In addition, it also decreased VEGF expression. Furthermore, GLP-1 promoted cell survival by increasing the anti-apoptotic protein Bcl-xl and the signaling pathway Akt/GSK3b/β-catenin. Finally, Ki67 results revealed that GLP-1 treatment could induce neurogenesis. In conclusion, the topical administration of GLP-1 reverts the impairment of the neurovascular unit by modulating essential pathways involved in the development of diabetic retinopathy (DR). These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of GLP-1 in early stages of DR.

scholarly journals mTORC1/rpS6 signaling complex modifies BTB transport function: an in vivo study using the adjudin model

2019 ◽  
Vol 317 (1) ◽  
pp. E121-E138 ◽  
Author(s):  
Ming Yan ◽  
Linxi Li ◽  
Baiping Mao ◽  
Huitao Li ◽  
Stephen Y. T. Li ◽  
...  
Keyword(s):  
Sertoli Cell ◽  
Sertoli Cells ◽  
Transfection Efficiency ◽  
Drug Dose ◽  
Site Directed Mutagenesis ◽  
Transport Function ◽  
Drug Bioavailability ◽  
Male Contraceptive ◽  
Signaling Complex

Studies have shown that the mTORC1/rpS6 signaling cascade regulates Sertoli cell blood-testis barrier (BTB) dynamics. For instance, specific inhibition of mTORC1 by treating Sertoli cells with rapamycin promotes the Sertoli cell barrier, making it “tighter.” However, activation of mTORC1 by overexpressing a full-length rpS6 cDNA clone (i.e., rpS6-WT, wild type) in Sertoli cells promotes BTB remodeling, making the barrier “leaky.” Also, there is an increase in rpS6 and p-rpS6 (phosphorylated and activated rpS6) expression at the BTB in testes at stages VIII–IX of the epithelial cycle, and it coincides with BTB remodeling to support the transport of preleptotene spermatocytes across the barrier, illustrating that rpS6 is a BTB-modifying signaling protein. Herein, we used a constitutively active, quadruple phosphomimetic mutant of rpS6, namely p-rpS6-MT of p-rpS6-S235E/S236E/S240E/S244E, wherein Ser (S) was converted to Glu (E) at amino acid residues 235, 236, 240, and 244 from the NH2 terminus by site-directed mutagenesis, for its overexpression in rat testes in vivo using the Polyplus in vivo jet-PEI transfection reagent with high transfection efficiency. Overexpression of this p-rpS6-MT was capable of inducing BTB remodeling, making the barrier “leaky.” This thus promoted the entry of the nonhormonal male contraceptive adjudin into the adluminal compartment in the seminiferous epithelium to induce germ cell exfoliation. Combined overexpression of p-rpS6-MT with a male contraceptive (e.g., adjudin) potentiated the drug bioavailability by modifying the BTB. This approach thus lowers intrinsic drug toxicity due to a reduced drug dose, further characterizing the biology of BTB transport function.

scholarly journals Nanotechnology for Topical Drug Delivery to the Anterior Segment of the Eye

2021 ◽  
Vol 22 (22) ◽  
pp. 12368
Author(s):  
Alexander Vaneev ◽  
Victoria Tikhomirova ◽  
Natalia Chesnokova ◽  
Ekaterina Popova ◽  
Olga Beznos ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Anterior Segment ◽  
Drug Carriers ◽  
Ocular Tissue ◽  
Eye Drops ◽  
Topical Drug Delivery ◽  
Natural Polymers ◽  
Drug Bioavailability ◽  
Sustained Drug Release

Topical drug delivery is one of the most challenging aspects of eye therapy. Eye drops are the most prevalent drug form, especially for widely distributed anterior segment eye diseases (cataracts, glaucoma, dry eye syndrome, inflammatory diseases, etc.), because they are convenient and easy to apply by patients. However, conventional drug formulations are usually characterized by short retention time in the tear film, insufficient contact with epithelium, fast elimination, and difficulties in overcoming ocular tissue barriers. Not more than 5% of the total drug dose administered in eye drops reaches the interior ocular tissues. To overcome the ocular drug delivery barriers and improve drug bioavailability, various conventional and novel drug delivery systems have been developed. Among these, nanosize carriers are the most attractive. The review is focused on the different drug carriers, such as synthetic and natural polymers, as well as inorganic carriers, with special attention to nanoparticles and nanomicelles. Studies in vitro and in vivo have demonstrated that new formulations could help to improve the bioavailability of the drugs, provide sustained drug release, enhance and prolong their therapeutic action. Promising results were obtained with drug-loaded nanoparticles included in in situ gel.

scholarly journals Effect of A 2-HP-β-Cyclodextrin Formulation on the Biological Transport and Delivery of Chemotherapeutic PLGA Nanoparticles

2020 ◽  
Author(s):  
Kangyu Zheng ◽  
Zeju Huang ◽  
Jiaying Huang ◽  
Xiangmei Liu ◽  
JUNFENG BAN ◽  
...  
Keyword(s):  
Drug Release ◽  
Cellular Uptake ◽  
Entrapment Efficiency ◽  
Plga Nanoparticles ◽  
Human Lung Cancer ◽  
Pharmacokinetic Analysis ◽  
Biological Transport ◽  
Sustained Drug Release

Abstract Background: The aim of this work was to develop a novel and feasible modification strategy by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodexrin (2-HP-β-CD) for enhancing the biological transport efficiency of paclitaxel (PTX)-loaded poly(lactide-co-glycolide)(PLGA) nanoparticles.Methods: PTX-loaded 2-HP-β-CD-modified PLGA nanoparticles (2-HP-β-CD/PLGA NPs) were prepared using the modified emulsion method. Nano-characteristics, drug release behavior, in vitro cytotoxicity, cellular uptake profiles and in vivo bio-behavior of the nanoparticles were then characterized. Results: Compared with the plain PLGA NPs, 2-HP-β-CD/PLGA NPs exhibited smaller particle sizes (151.03±1.36 nm), increased entrapment efficiency (~49.12% increase) and sustained drug release. When added to A549 human lung cancer cells, compared with PLGA NPs, 2-HP-β-CD/PLGA NPs exhibited higher cytotoxicity in MTT assays and improved cellular uptake efficiency. Pharmacokinetic analysis showed that the AUC value of 2-HP-β-CD/PLGA NPs was 2.4-fold higher than commercial Taxol® and 1.7-fold higher than plain PLGA NPs. In biodistribution assays, 2-HP-β-CD/PLGA NPs exhibited excellent stability in the circulation.Conclusions: The results of this study suggest that formulation contains 2-HP-β-CD can prolong PTX release, enhance drug transpot efficiency and serve as a potential tumor targeting system for PTX.

scholarly journals Ex Vivo Permeation of Carprofen Vehiculated by PLGA Nanoparticles through Porcine Mucous Membranes and Ophthalmic Tissues

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 355 ◽  
Author(s):  
Lídia Gómez-Segura ◽  
Alexander Parra ◽  
Ana Cristina Calpena-Campmany ◽  
Álvaro Gimeno ◽  
Immaculada Gómez de Aranda ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Cell Structure ◽  
Topical Administration ◽  
Plga Nanoparticles ◽  
In Vivo Studies ◽  
Ex Vivo Permeation ◽  
Mucous Membranes ◽  
Anti Inflammatory ◽  
Almost All

(1) Background: Carprofen (CP), 2-(6-chlorocarbazole) propionic acid, is used as an anti-inflammatory, analgesic and anti-pyretic agent and it belongs to the family of non-steroidal anti-inflammatory drugs (NSAIDs). CP has some adverse reactions in systemic administration; for this reason, topical administration with CP nanoparticles (CP-NPs) can be an optimal alternative. The main objective of this work is the investigation of ex vivo permeation of CP through different types of porcine mucous membranes (buccal, sublingual and vaginal) and ophthalmic tissues (cornea, sclera and conjunctiva) to compare the influence of CP-NPs formulation over a CP solution (CP-Solution). (2) Methods: The ex vivo permeation profiles were evaluated using Franz diffusion cells. Furthermore, in vivo studies were performed to verify that the formulations did not affect the cell structure and to establish the amount retained (Qr) in the tissues. (3) Results: Permeation of CP-NPs is more effective in terms of drug retention in almost all tissues (with the exception of sclera and sublingual). In vivo studies show that neither of the two formulations affects tissue structure, so both formulations are safe. (4) Conclusions: It was concluded that CP-NPs may be a useful tool for the topical treatment of local inflammation in veterinary and human medicine.

scholarly journals Recent Advances in Topical Therapeutics for Vitreoretinal Diseases

2015 ◽  
Vol 8 (1) ◽  
pp. 60 ◽  
Author(s):  
Jonathan M Gibson ◽  
Samantha McGinnigle ◽  
◽  
Keyword(s):  
Topical Administration ◽  
Eye Drops ◽  
Topical Drug Delivery ◽  
Defence Mechanisms ◽  
Sustained Drug Release ◽  
Physiology And Biochemistry ◽  
Vitreoretinal Diseases ◽  
Therapeutic Doses ◽  
Experimental Use ◽  
Near Future

Eye drops are convenient for patients, but achieving therapeutic doses and maintaining sustained drug release without frequent re-application to treat diseases of the retina has been largely unsuccessful. Topical administration of drugs is hindered by the anatomy, physiology, and biochemistry of the eye and its highly effective defence mechanisms. Advances in nanotechnology have led to the experimental use of topical permeation-enhancing liposomes, emulsions, and microspheres to enhance absorption and penetration of drugs across membranes; allow controlled release of the drug; and to target drugs at distinct tissues to allow sufficient local bioavailability. In the near future it is hoped that improved technologies may provide means of sustained topical drug delivery for retinal therapy, with improved side-effect profiles and reduced cost compared with currently available clinical treatments.

scholarly journals Gelatin Nanoparticles-HPMC Hybrid System for Effective Ocular Topical Administration of Antihypertensive Agents

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 306
Author(s):  
Sergio Esteban-Pérez ◽  
Vanessa Andrés-Guerrero ◽  
José Javier López-Cano ◽  
Irene Molina-Martínez ◽  
Rocio Herrero-Vanrell ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Hybrid System ◽  
Drug Loading ◽  
Topical Administration ◽  
Hypotensive Effect ◽  
Maximum Effect ◽  
Gelatin Nanoparticles ◽  
Drug Bioavailability ◽  
Promising Alternative

The increment in ocular drug bioavailability after topical administration is one of the main challenges in pharmaceutical technology. For several years, different strategies based on nanotechnology, hydrogels or implants have been evaluated. Nowadays, the tolerance of ophthalmic preparations has become a critical issue and it is essential to the use of well tolerated excipients. In the present work, we have explored the potential of gelatin nanoparticles (GNPs) loaded with timolol maleate (TM), a beta-adrenergic blocker widely used in the clinic for glaucoma treatment and a hybrid system of TM-GNPs included in a hydroxypropyl methylcellulose (HPMC) viscous solution. The TM- loaded nanoparticles (mean particle size of 193 ± 20 nm and drug loading of 0.291 ± 0.019 mg TM/mg GNPs) were well tolerated both in vitro (human corneal cells) and in vivo. The in vivo efficacy studies performed in normotensive rabbits demonstrated that these gelatin nanoparticles were able to achieve the same hypotensive effect as a marketed formulation (0.5% TM) containing a 5-fold lower concentration of the drug. When comparing commercial and TM-GNPs formulations with the same TM dose, nanoparticles generated an increased efficacy with a significant (p < 0.05) reduction of intraocular pressure (IOP) (from 21% to 30%) and an augmentation of 1.7-fold in the area under the curve (AUC)(0–12h). On the other hand, the combination of timolol-loaded nanoparticles (TM 0.1%) and the viscous polymer HPMC 0.3%, statistically improved the IOP reduction up to 30% (4.65 mmHg) accompanied by a faster time of maximum effect (tmax = 1 h). Furthermore, the hypotensive effect was extended for four additional hours, reaching a pharmacological activity that lasted 12 h after a single instillation of this combination, and leading to an AUC(0–12h) 2.5-fold higher than the one observed for the marketed formulation. According to the data presented in this work, the use of hybrid systems that combine well tolerated gelatin nanoparticles and a viscous agent could be a promising alternative in the management of high intraocular pressure in glaucoma.

scholarly journals Dexibuprofen Biodegradable Nanoparticles: One Step Closer towards a Better Ocular Interaction Study

Nanomaterials ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 720 ◽  
Author(s):  
Elena Sánchez-López ◽  
Gerard Esteruelas ◽  
Alba Ortiz ◽  
Marta Espina ◽  
Josefina Prat ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Plga Nanoparticles ◽  
Ocular Inflammation ◽  
Patient Treatment ◽  
Eye Drops ◽  
Drug Induced ◽  
Ocular Tissues ◽  
Suitable Alternative ◽  
Anti Inflammatory

Ocular inflammation is one of the most prevalent diseases in ophthalmology, which can affect various parts of the eye or the surrounding tissues. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, are commonly used to treat ocular inflammation in the form of eye-drops. However, their bioavailability in ocular tissues is very low (less than 5%). Therefore, drug delivery systems such as biodegradable polymeric PLGA nanoparticles constitute a suitable alternative to topical eye administration, as they can improve ocular bioavailability and simultaneously reduce drug induced side effects. Moreover, their prolonged drug release can enhance patient treatment adherence as they require fewer administrations. Therefore, several formulations of PLGA based nanoparticles encapsulating dexibuprofen (active enantiomer of Ibuprofen) were prepared using the solvent displacement method employing different surfactants. The formulations have been characterized and their interactions with a customized lipid corneal membrane model were studied. Ex vivo permeation through ocular tissues and in vivo anti-inflammatory efficacy have also been studied.

scholarly journals Investigation of Combined Cyclodextrin and Hydrogel Formulation for Ocular Delivery of Dexamethasone Acetate by Means of Experimental Designs

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 249 ◽  
Author(s):  
Roseline Mazet ◽  
Luc Choisnard ◽  
Delphine Levilly ◽  
Denis Wouessidjewe ◽  
Annabelle Gèze
Keyword(s):  
Ex Vivo ◽  
Aqueous Solubility ◽  
Eye Drops ◽  
Ocular Delivery ◽  
Drug Bioavailability ◽  
Corneal Inflammation ◽  
Dexamethasone Acetate ◽  
Great Propensity

Dexamethasone acetate (DXMa) has proven its efficiency to treat corneal inflammation, without a great propensity to increase intraocular pressure. Unfortunately, its poor aqueous solubility, associated with a rapid precorneal elimination, results in a low drug bioavailability and a low penetration after topical ocular administration. The main objective of this study was to improve the apparent aqueous solubility of DXMa using cyclodextrins. First, hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) were used to enhance DXMa concentration in aqueous solution. The β and γ HPCD derivatives allowed the increase of the DXMa amount in solution at 25 °C by a factor of 500 and 1500, respectively. Second, with the aim of improving the persistence of the complex solution after instillation in the eye, the formulations of DXMa-based CD solutions with marketed ophthalmic gels (CELLUVISC®, GEL-LARMES®, and VISMED®) were investigated and optimized by means of special cubic mixture designs, allowing the defining of mixed gels loaded with 0.7% (HPβCD) and 2% (HPγCD) DXMa with osmolality within acceptable physiological range. Finally, in vitro drug release assays from the mixed gels were performed and compared with reference eye drops. Similarly to MAXIDEX® and DEXAFREE®, in the case of mixed gel containing HPβCD, more than 90% of the drug was released within 2 h, while in mixed gel containing HPγCD, the release of DXMa was partial, reaching ≈60% in 2 h. This difference will have to be further addressed with ex vivo and in vivo ocular delivery experiments.

scholarly journals Magnetically Assisted Drug Delivery of Topical Eye Drops Maintains Retinal Function In Vivo in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1650
Author(s):  
Marco Bassetto ◽  
Daniel Ajoy ◽  
Florent Poulhes ◽  
Cathy Obringer ◽  
Aurelie Walter ◽  
...  
Keyword(s):  
Drug Targeting ◽  
Biological Effects ◽  
Genetic Disorder ◽  
Topical Administration ◽  
Magnetic Drug Targeting ◽  
Eye Drops ◽  
Non Invasive ◽  
Assisted Delivery ◽  
Magnetically Assisted

Barded-Biedl syndrome (BBS) is a rare genetic disorder with an unmet medical need for retinal degeneration. Small-molecule drugs were previously identified to slow down the apoptosis of photoreceptors in BBS mouse models. Clinical translation was not practical due to the necessity of repetitive invasive intravitreal injections for pediatric populations. Non-invasive methods of retinal drug targeting are a prerequisite for acceptable adaptation to the targeted pediatric patient population. Here, we present the development and functional testing of a non-invasive, topical, magnetically assisted delivery system, harnessing the ability of magnetic nanoparticles (MNPs) to cargo two drugs (guanabenz and valproic acid) with anti-unfolded protein response (UPR) properties towards the retina. Using magnetic resonance imaging (MRI), we showed the MNPs’ presence in the retina of Bbs wild-type mice, and their photoreceptor localization was validated using transmission electron microscopy (TEM). Subsequent electroretinogram recordings (ERGs) demonstrated that we achieved beneficial biological effects with the magnetically assisted treatment translating the maintained light detection in Bbs−/− mice (KO). To our knowledge, this is the first demonstration of efficient magnetic drug targeting in the photoreceptors in vivo after topical administration. This non-invasive, needle-free technology expands the application of SMDs for the treatment of a vast spectrum of retinal degenerations and other ocular diseases.

Sign in / Sign up

Export Citation Format

Share Document