Potentiation of Brain Bioavailability Using Thermoreversible Cubosomal Formulation.

The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 µg/mL), Cmax (368.07 ± 0.23 µg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.

Preparation and in vivo and ex vivo studies of sirolimus nano-in-situ gel ophthalmic formulation.

Sirolimus (SR) is a macrolide with antifungal and antitumor immunosuppressant properties, classified as a selective inhibitor of mammalian target of rapamycin (mTOR). In this study, an ionic in situ gel of SR (SR-SUS-ISG) was formulated using gellan gum, exhibiting stability regardless of temperature and pH variations, causing minimal irritation. Harnessing the physiological conditions of the eye, SR-SUS-ISG underwent gelation upon contact with ions, increasing drug viscosity and prolonging retention on the ocular surface. Concurrently, SR-SUS-ISG displayed favorable shear dilution properties, reducing viscosity at ambient temperature, enhancing fluidity, and facilitating convenient packaging and transport. Biocompatibility assessments on both human corneal epithelial cells and rabbit eyes demonstrated that SR-SUS-ISG could well be tolerated. Pharmacokinetic investigations in rabbit ocular aqueous humor revealed sustained release, improved corneal penetration, and enhanced bioavailability. Additionally, in a rat corneal alkali burn model, SR-SUS-ISG exhibited inhibitory effects on corneal neovascularization, associated with decreased levels of the inflammatory factors VEGF and MMPs. These findings suggested that SR-SUS-ISG held promise as an effective ocular drug delivery system.

Intranasal administration of innovative triamcinolone acetonide encapsulated cubosomal in situ gel: formulation and characterization.

AIM: The primary objective of the research was to develop a cubosomal in situ gel encapsulated with Triamcinolone acetonide (TCA) in order to enhance its penetration through the blood-brain barrier (BBB) when administered via the intranasal route, thus enabling efficient and rapid action. METHOD: Cubosomes were formulated by top-down approach using glyceryl monooleate (GMO), using pluronics127 (PF127) and polyvinyl alcohol (PVA) in varying proportions based on the Box-Behnken design. High resolution transmission electron microscopy (HR-TEM) analysis confirmed the morphology of the cubosomes. The in situ gel was formulated and optimized. Experiments involving ex vivo permeation and histopathology analyses were undertaken to evaluate drug permeation and tissue effects. RESULTS: The cubosomes exhibited a particle size (PS) of 197.9 nm, zeta potential (ZP) of -31.11 mV, and entrapment efficacy (EE) of 84.31%, with low deviation. Batch F4 (19% PF127) showed favorable results. In vitro and ex vivo permeation studies revealed drug release of 78.59% and 76.65%, respectively, after 8 h. Drug release followed the Hixson Crowell model of release kinetics. The histopathological examination revealed no signs of toxicity or adverse effects on the nasal mucosa of the sheep. The formulation exhibited short-term stability, maintaining its integrity and properties when stored at room temperature. CONCLUSION: The utilization of an intranasal cubosomal in situ gel encapsulated with TCA was anticipated to lower intracranial pressure and improve patient adherence by offering effective relief for individuals suffering from Brain edema. This efficacy is attributed to its rapid onset of action and its safe and well-tolerated dosage form.

Formulation development and evaluation of nasal in situ gel of promethazine hydrochloride.

OBJECTIVE: The present work aims to develop mucoadhesive thermosensitive nasal in situ gel for Promethazine hydrochloride using quality by design (QbD) approach. It can reduce nasal mucociliary clearance (MCC) and increase residence of the drug on nasal mucosa. This might increase drug absorption to improve bioavailability of the drug as compared to oral dosage form. SIGNIFICANCE: Promethazine hydrochloride is an antiemetic drug administered by oral, parenteral and rectal routes. These routes have poor patient compliance or low bioavailability. Nasal route is a better alternative as it has large surface area, high drug absorption rate and no first pass effect. Its only limitation is short drug retention time due to MCC. By formulating a mucoadhesive in situ gel, the MCC can be reduced, and drug absorption will be prolonged. Thus, improving bioavailability. METHOD: In-situ gel was prepared by cold method having material attributes as concentration of Poloxamer 407 (X1) as gelling agent and hydroxypropyl methyl cellulose K4M (X2) as mucoadhesive agent. Critical Quality Attributes (CQA) were gelation temperature, mucoadhesive force and ex-vivo diffusion. Central composite design (CCD) was adopted for optimization. RESULT: Optimized formulation satisfied all the CQA significant for nasal administration. Moreover, the formulation was found to be stable in accelerated stability studies for 3 months. CONCLUSION: It can be concluded that since the drug can easily permeate through nasal mucosa and can gain access directly in the brain without undergoing first pass metabolism along with increased residence due to mucoadhesion, mucoadhesive in situ gel has potential to increase drug bioavailability.

A new approach for the treatment of Alzheimer's disease: insulin-quantum dots.

The potential use of insulin supplementation for Alzheimer's Disease (AD) was aimed to investigate and explore CQDs as an alternative delivery system. CQDs were produced by microwave and characterised. Insulin-loaded Ins-CQDs and in-situ Gel-Ins-CQDs were developed. The in vitro release kinetics, penetrations of insulin through excised sheep nasal mucosa were determined. Toxicity of CQDs were calculated on SH-SY5Y cells. The stability and usability of the prepared formulations were assessed. The insulin release from the solution was 70.75% after 3 hours, while it was 37.51% for in-situ Gel-Ins-CQDs. IC50 value was 52 µM. The mean particle diameters of Ins-CQDs and in-situ Gel-Ins-CQDs varied between 8.35 ± 0.19 to 8.75 ± 0.03 nm during a 6-month period. Zeta potentials ranged from -31.51 ± 1.39 to -24.43 ± 0.26 mV, and PDI values were between 9.8 ± 0.01 to 5.3 ± 3.2%(SD, n = 3) for Ins-CQDs and in-situ Gel-Ins-CQDs, respectively.Our results show that Gel-Ins-CQDs represented a controlled release over time and can be used for AD through the nasal route.

Fluconazole-Loaded Ibuprofen In Situ Gel-Based Oral Spray for Oropharyngeal Candidiasis Treatment.

Oral candidiasis is a fungal infection affecting the oral mucous membrane, and this research specifically addresses on a localized treatment through fluconazole-loaded ibuprofen in situ gel-based oral spray. The low solubility of ibuprofen is advantageous for forming a gel when exposed to an aqueous phase. The 1% w/w fluconazole-loaded in situ gel oral sprays were developed utilizing various concentrations of ibuprofen in N-methyl pyrrolidone. The prepared solutions underwent evaluation for viscosity, surface tension, contact angle, water tolerance, gel formation, interface interaction, drug permeation, and antimicrobial studies. The higher amount of ibuprofen reduced the surface tension and retarded solvent exchange. The use of 50% ibuprofen as a gelling agent demonstrated prolonged drug permeation for up to 24 h. The incorporation of Cremophor EL in the formulations resulted in increased drug permeation and exhibited effective inhibition against Candida albicans, Candida krusei, Candida lusitaniae, and Candida tropicalis. While the Cremophor EL-loaded formulation did not exhibit enhanced antifungal effects on agar media, its ability to facilitate the permeation of fluconazole and ibuprofen suggested potential efficacy in countering Candida invasion in the oral mucosa. Moreover, these formulations demonstrated significant thermal inhibition of protein denaturation in egg albumin, indicating anti-inflammatory properties. Consequently, the fluconazole-loaded ibuprofen in situ gel-based oral spray presents itself as a promising dosage form for oropharyngeal candidiasis treatment.

Quercetin-Loaded Nanostructured Lipid Carrier In Situ Gel for Brain Targeting Through Intranasal Route: Formulation, In Vivo Pharmacokinetic and Pharmacodynamic Studies.

Quercetin (QT) shows potential for protecting against neurodegenerative diseases like Alzheimer's. However, its limited bioavailability and instability in physiological pH hinder its clinical use. The purpose of this work is to construct QT-filled nanostructured lipid carriers (QT-NLC) intranasal in situ gel to enhance pharmacokinetic and pharmacodynamic performance. NLCs were developed using a melt emulsification-high-pressure homogenization and were optimized using design expert software with the Box-Behnken design. NLCs were then incorporated into an in situ gel based on Lutrol F127 and further characterized. The pharmacodynamics of the formulation was evaluated in neurodegeneration induced by trimethyl tin (TMT) Wistar rats. The optimized QT in situ gel had spherical shape, entrapment efficiency of 96.1 ± 4.40%, and in vitro drug release of 83.74 ± 1.40%. The mean particle size was 123.3 ± 5.46 nm. After intranasal administration, in vivo single-dose pharmacokinetic studies demonstrated a significant therapeutic concentration of drug in CNS, having Cmax 183.41 ± 11.76 ng/mL and Tmax of 2 h. The more brain targeting efficiency of NLCs was proved by the developed QT in situ gel, which had a higher drug targeting efficiency (DTE) of 117.47% and drug targeting potential (DTP) of 88.9%. As compared to the neurodegeneration control group, the QT in situ gel-treated group had significantly decreased escape latency and pathlength. Biochemical analysis and histological investigations demonstrated that QT in situ gel exhibited superior anti-Alzheimer's potential compared to standard drug, donepezil. The promising results of the developed and optimized intranasal QT in situ gel suggest its potential and can be used in Alzheimer's disease management.

Mixed-Micelle in Situ Gel as a Candidate for Oral Inflammatory Ulcerative Diseases.

The current treatment for oral inflammatory ulcerative diseases has limitations. In situ forming hydrogels have shown great potential to deliver therapeutic substances for drug delivery to the buccal cavity. This study aimed to prepare and characterize lipid- and surfactant-based mixed micelle in situ gel (MIG) and evaluate whether it can offer more favorable properties than the in situ gel for effective treatment of the disease. Dexamethasone was incorporated into the MIGs particles, based on Poloxamer 407 and chitosan. The lower gelation time at 37 ℃ was considered a criterion to select superior formulations among the different lipid- and surfactant-based candidates. Further characterization was performed to evaluate the opted formulations regarding morphology, physical stability, rheology, texture, and release profile. All formulations were thermoresponsive and had a shorter gelation time as the temperature increased. Dexamethasone was released in a highly controlled manner, and morphological evaluation revealed that the mixed micelle in situ gels had spherical nanoparticles. Thixotropic behavior was observed in all MIGs, indicating a prolonged retention time of the formulation after oral administration. This study has shown that among different MIGs, the one with oleic acid is a more promising candidate than the in situ gel and other MIGs for drug delivery to the buccal cavity.

Assembly of In-Situ Gel Containing Nano-Spanlastics of an Angiotensin II Inhibitor as a Novel Epitome for Hypertension Management: Factorial Design Optimization, In-vitro Gauging, Pharmacokinetics, and Pharmacodynamics Appraisal.

More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.

Formulation of Metoclopramide Hydrochloride-Loaded Lipid Carriers by QbD Approach for Combating Nausea: Safety and Bioavailability Evaluation in New Zealand Rabbit.

The focus of the research was to overcome the limitations of metoclopramide (MTC) when administered intranasally. The aim was to improve its bioavailability, increase patient compliance, and prolong its residence time in the nasal cavity. MTC-loaded liposomes were prepared by applying the film hydration method. A study was conducted to determine how formulation variables affected encapsulation efficiency (EE %), mean particle size (MPS), and zeta potential (ZP). The MTC-liposomes were further loaded into the in situ gel (gellan gum) for longer residence times following intranasal administration. pH, gelling time, and in vitro release tests were conducted on the formulations produced. In vivo performance of the MTC-loaded in situ gels was appraised based on disparate parameters such as plasma peak concentration, plasma peak time, and elimination coefficient compared to intravenous administration. When the optimal liposome formulation contained 1.98% of SPC, 0.081% of cholesterol, 97.84% of chloroform, and 0.1% of MTC, the EE of MTC was 83.21%, PS was 107.3 nm. After 5 h, more than 80% of the drug was released from MTC-loaded liposome incorporated into gellan gum in situ gel formulation (Lip-GG), which exhibited improved absorption and higher bioavailability compared to MTC loaded into gellan gum in situ gel (MTC-GG). Acceptable cell viability was also achieved. It was found out that MTC-loaded liposomal in situ gel formulations administered through the nasal route could be a better choice than other options due to its ease of administration, accurate dosing, and higher bioavailability in comparison with MTC-GG.

Design and Evaluation of a Dual-Sensitive In Situ Gel for the Controlled Release of Pranoprofen.

Currently, the marketed ophthalmic preparations of pranoprofen (PF) are mainly eye drops, but due to the special clearance mechanism of the eye and corneal reflex, the contact time between the drug and the focal site is short, most of the drug is lost, and the bioavailability is less than 5%. In the present study, an in situ gel eye drop containing no bacteriostatic agent and sensitive to temperature and ions was designed for delivery of PF. It was demonstrated to meet the criteria for ophthalmic preparations by characterization such as appearance content sterility. Ocular irritation tests showed a favorable safety profile. In vivo ocular retention time experiments showed that the ocular retention time of the pranoprofen gel was 4.41 times longer than that of commercially available drops (Pranopulin®), and the nasal tear excretion of the pranoprofen gel was lower than that of Pranopulin®, which suggests that the drug loss was reduced relative to that of the drops. The efficacy of the pranoprofen gel against tincture of cayenne pepper-induced corneal and conjunctival inflammation was examined using Pranopulin® as a control and in conjunction with inflammation scores, H&E slice results, and levels of IL-1ß, IL-6, and TNF-α. The results showed that pranoprofen gel and Pranololin® had significant efficacy in the treatment of corneal and conjunctival inflammation, and the anti-inflammatory effect of pranoprofen gel was superior to that of Pranololin®. This study provides a new option for the treatment of corneal and conjunctival inflammation.

[Preparation and characterization of co-loaded indocyanine green and elemene nano-emulsion in situ gel and its effect on proliferation of breast cancer MCF-7 cells].

This study aims to prepare co-loaded indocyanine green(ICG) and elemene(ELE) nano-emulsion(NE) in situ gel(ICG-ELE-NE-gel) and evaluate its physicochemical properties and antitumor activity in vitro. ICG-ELE-NE-gel was prepared by aqueous phase titration and cold solution methods, followed by characterization of the morphology, particle size, corrosion, and photothermal conversion characteristics. The human breast cancer MCF-7 cells were taken as the model, combined with 808 nm laser irradia-tion. Cell inhibition rate test and cell uptake test were performed. ICG-ELE-NE was spherical and uniform in size. The average particle size and Zeta potential were(85.61±0.35) nm and(-21.4±0.6) mV, respectively. The encapsulation efficiency and drug loading rate were 98.51%±0.39% and 10.96%±0.24%, respectively. ICG-ELE-NE-gel had a good photothermal conversion effect and good photothermal stability. The dissolution of ICG-ELE-NE-gel had both temperature and pH-responsive characteristics. Compared with free ELE, ICG-ELE-NE-gel combined with near-infrared light irradiation significantly enhanced the inhibitory effect on MCF-7 cells and could be uptaken in large amounts by MCF-7 cells. ICG-ELE-NE-gel was successfully prepared, and its antitumor activity was enhanced after 808 nm laser irradiation.

Preparation and In Vitro and In Vivo Evaluation of Rectal In Situ Gel of Meloxicam Hydroxypropyl-ß-cyclodextrin Inclusion Complex.

Meloxicam (MLX) is one of the most effective NSAIDs, but its poor water solubility and low bioavailability limit its clinical application. In this study, we designed a thermosensitive in situ gel of the hydroxypropyl-ß-cyclodextrin inclusion complex (MLX/HP-ß-CD-ISG) for rectal delivery to improve bioavailability. The best method for preparing MLX/HP-ß-CD was the saturated aqueous solution method. The optimal inclusion prescription was optimized using an orthogonal test, and the inclusion complex was evaluated via PXRD, SEM, FTIR and DSC. Then, MLX/HP-ß-CD-ISG was characterized regarding the gel properties, release in vitro, and pharmacokinetics in vivo. The inclusion rate of the inclusion complex obtained via the optimal preparation process was 90.32 ± 3.81%. The above four detection methods show that MLX is completely embedded in the HP-ß-CD cavity. The developed MLX/HP-ß-CD-ISG formulation has a suitable gelation temperature of 33.40 ± 0.17 °C, a gelation time of 57.33 ± 5.13 s, pH of 7.12 ± 0.05, good gelling ability and meets the requirements of rectal preparations. More importantly, MLX/HP-ß-CD-ISG significantly improved the absorption and bioavailability of MLX in rats, prolonging the rectal residence time without causing rectal irritation. This study suggests that the MLX/HP-ß-CD-ISG can have a wide application prospect with superior therapeutic benefits.

Development of favipiravir loaded PLGA nanoparticles entrapped in in-situ gel for treatment of Covid-19 via nasal route.

In 2019 the emergence of SARS-COV-2 caused pandemic situation worldwide and claimed ∼6.4 M lives (WHO 2022). Favipiravir (FAV) is recommended as a therapy for Covid-19 which belongs to BCS class III with a short half-life of 2-5.5h. Thus, the objective of current study was the development of favipiravir loaded PLGA nanoparticles (NPs) by box-behnken design. Moreover, these NPs were entrapped in thermosensitive gel to increase the permeation through nasal route. The nanoparticles exhibit particle size of 175.6 ± 2 nm with >70 ± 0.5 %EE. NPs showed PDI (0.130) and zeta potential (-17.1 mV) suggesting homogeneity and stability of NPs. DSC, XRD, and FTIR studies concluded absence of any interaction of FAV and the excipients. SEM and AFM studies demonstrated spherical morphology of NPs with smooth surface. The NPs entrapped in-situ gel showed clarity and pH 5.5-6.1. The gelation temperature of NPs dispersed in-situ gel was found in the range of 35 °C -37 °C. The gel has viscosity in range of 34592-4568 cps. The texture analysis profile of gel showed good gelling properties. Dissolution study suggested a sustained release of FAV from NPs (24h) and NPs dispersed gel (32h) as compared to FAV solution (4h). The gel showed good mucoadhesion properties (9373.9 dyne/cm2). Ex-vivo permeation through nasal mucosa of goat elucidated NPs dispersed gel demonstrated significantly higher permeation than solution and NPs. Therefore, it would be a prospective formulation to combat Covid-19 infection with high patient compliance.

Green polymer altered in-situ gel oral liquid sustainable release preparation of vildagliptin suitable for dysphagic diabetic patients: assessment in-vitro & in-vivo.

PURPOSE: This work aimed to fabricate alginate based in-situ gelling matrix of vildagliptin improved by calcium and carboxy methyl cellulose (CMC) for appropriate adjustment of the onset and duration of action. This easy-to-swallow thickened liquid preparation aimed to improve compliance for dysphagic or elderly diabetic patients. METHODS: Vildagliptin dispersions containing alginate were fabricated in the presence or absence of calcium chloride to assess the effect of calcium ion, then a matrix containing 1.5% w/v of sodium alginate with calcium was further examined after the addition of CMC with different concentrations ranging from 0.1% to 0.3%. The viscosity, gelling forming property, Differential scanning calorimetry, and in-vitro drug release were assessed before monitoring the hypoglycemic effect of the selected formulation. RESULTS: In-situ gel matrixes were fabricated at gastric pH with and without calcium ions. The best formula concerning viscosity and the gel-forming property was achieved with higher CMC concentrations, which in turn decreased the rate of vildagliptin release in stimulated gastric pH. In-vivo results confirmed the extended hypoglycemic effect of the vildagliptin in-situ gelling matrix compared to the vildagliptin aqueous solution. CONCLUSION: This study represents a green polymeric-based in-situ gel as a liquid oral retarded release preparation intended for reducing dose frequency, easier administration of vildagliptin, and improving compliance in geriatric and dysphagic diabetic patients.

Cubosome-based thermosensitive in situ gelling system for intranasal administration of lamotrigine with enhanced antiepileptic efficacy.

Lamotrigine (LTG) is a second-generation antiepileptic drug that belongs to Biopharmaceutics Classification System (BCS) class II. LTG has a low probability of crossing the BBB if administered orally. This study was designed to fabricate LTG cubosomal dispersion that is further loaded in a thermosensitive in situ gel to increase nasal residence time and enhance drug absorption across the nasal mucosal membrane. LTG-loaded cubosomes exhibited an entrapment efficiency ranging from 24.83% to 60.13%, a particle size ranging from 116.2 to 197.6 nm, and a zeta potential ≤-25.5 mV. The selected LTG-loaded cubosomal formulation was loaded in a thermosensitive in situ gel (cubogel) employing different concentrations of poloxamer 407. In vitro release study revealed sustained drug release from cubosomal and cubogel compared with free drug suspension. In vivo studies revealed enhanced antiepileptic efficacy of LTG cubogel and LTG cubosomes compared with free drug in rats with pilocarpine-induced epilepsy by stimulating the release of gamma-aminobutyric acid (GABA), total antioxidant capacity (TAC), and serotonin and by inhibiting the release of Ca2+, dopamine, acetylcholine (Ach), C-reactive protein (CRP), and glial fibrillary acidic protein (GFAP). LTG cubogel exhibited superior activity over LTG cubosomes. These findings reveal that the developed cubosomal thermosensitive in situ gel can enhance the antiepileptic efficacy of LTG via the intranasal route.

Novel Sprayable Thermosensitive Benzydamine Hydrogels for Topical Application: Development, Characterization, and In Vitro Biological Activities.

Benzydamine hydrochloride (BZD) having analgesic, anesthetic, and anti-inflammatory effects is used orally or topically in the treatment of disorders such as joint inflammation and muscle pain. Within the scope of this study, sprayable thermosensitive BZD hydrogels were developed using thermoresponsive poloxamers to avoid systemic side effects and to provide better compliance for topical administration. Also, hydroxypropyl methyl cellulose (HPMC) was employed to improve the mechanical strength and bioadhesive properties of the hydrogel. The addition of BZD generally decreased the viscosity of the formulations (p < 0.05), while increasing the gelation temperature (p < 0.05). The formulations that did not have any clogs or leaks in the nozzle of the bottle during the spraying process were considered lead formulations. To spray the formulations easily, it was found that the viscosity at RT should be less than 200 mPa·s, and their gelation temperature should be between 26 and 34°C. Increasing HPMC and poloxamer improved bioadhesion. The amount of HPMC and poloxamers did not cause a significant change in the release characteristics of the formulations (p > 0.05); the release profiles of BZD from the formulations were similar according to model-independent kinetic (f2 > 50). HPMC and poloxamers had important roles in the accumulation of BZD in the skin. In vitro biological activity studies demonstrated that the formulations presented their anti-inflammatory activity with TNF-α inhibition but did not have any effect on the inhibition of COX enzymes as expected. As a result, thermosensitive hydrogels containing BZD might be an appropriate alternative, providing an advantage in terms of easier application compared to conventional gels.

Ocular Drug Delivery: a Comprehensive Review.

The human eye is a sophisticated organ with distinctive anatomy and physiology that hinders the passage of drugs into targeted ophthalmic sites. Effective topical administration is an interest of scientists for many decades. Their difficult mission is to prolong drug residence time and guarantee an appropriate ocular permeation. Several ocular obstacles oppose effective drug delivery such as precorneal, corneal, and blood-corneal barriers. Routes for ocular delivery include topical, intravitreal, intraocular, juxtascleral, subconjunctival, intracameral, and retrobulbar. More than 95% of marketed products exists in liquid state. However, other products could be in semi-solid (ointments and gels), solid state (powder, insert and lens), or mixed (in situ gel). Nowadays, attractiveness to nanotechnology-based carries is resulted from their capabilities to entrap both hydrophilic and lipophilic drugs, enhance ocular permeability, sustain residence time, improve drug stability, and augment bioavailability. Different in vitro, ex vivo, and in vivo characterization approaches help to predict the outcomes of the constructed nanocarriers. This review aims to clarify anatomy of the eye, various ocular diseases, and obstacles to ocular delivery. Moreover, it studies the advantages and drawbacks of different ocular routes of administration and dosage forms. This review also discusses different nanostructured platforms and their characterization approaches. Strategies to enhance ocular bioavailability are also explained. Finally, recent advances in ocular delivery are described.

In Vitro and In Vivo Evaluation of Metformin Hydrochloride Hydrogels Developed with Experimental Design in the Treatment of Burns.

Burns alter the normal skin barrier and affect various host defense processes that help prevent infections. An ineffective repair process can lead to serious damage, such as the onset of an infection or skin loss, which can then harm the surrounding tissues and ultimately the entire organism. This study aims to prepare in situ gels containing metformin hydrochloride, a compound known for its wound healing properties. To achieve this, in situ gels were prepared using three different gelling agents (Poloxamer 407®, Carbopol 934®, and sodium carboxymethyl cellulose (Na-CMC)) and three different concentrations of metformin hydrochloride (4 mg/g, 6 mg/g, and 8 mg/g), which were optimized through experimental design. Metformin concentration and gelling agent type were independent variables, and the loaded amount and the percentage of metformin released after 150 min were chosen as dependent variables in the optimization process. After determining the optimum values of the dependent variables according to the ANOVA analysis results, in vivo studies were conducted with optimized hydrogel formulations. Two groups, each consisting of seven Wistar rats with a burn model, were treated with metformin-poloxamer 407® gels at doses of 4 mg/g and 8 mg/g for 29 days. The results were then compared to untreated and placebo gel groups. Rats treated with in situ Poloxamer 407® hydrogels containing metformin hydrochloride showed a significant reduction in the size of the burned area after 29 days of treatment. However, for a comprehensive understanding of the wound healing mechanism, further studies such as immuno-histochemical and cell culture studies are needed.

Optimization of In Situ Gel-Forming Chlorhexidine-Encapsulated Polymeric Nanoparticles Using Design of Experiment for Periodontitis.

Periodontitis is a chronic inflammatory disease of the gums caused by pathogenic microorganisms damaging and destroying periodontal tissues. Chlorhexidine digluconate (CHX) is a commonly used antimicrobial agent for the treatment of periodontitis. However, it has many drawbacks, such as toxicity due to the high dosage required, low prolonged release, and low adhesion in the periodontal pocket. The objective of this study was to develop and optimize CHX-encapsulated polymeric nanoparticles (NPs) loaded into in situ gel-forming (ISGF) using design of experiment (DoE) to improve the treatment of periodontitis and overcome these limitations. CHX-NPs were optimized from 0.046%w/v chitosan, 0.05%w/w gelatin, and 0.25%w/w CHX. After that, the optimized of CHX-NPs was loaded into a thermosensitive ISGF, which was a mixture of 15%w/v Poloxamer 407 and 1% hydroxypropyl methylcellulose (HPMC). The optimized CHX-NPs, loaded into ISGF, was evaluated by measuring gelling temperature and time, pH, viscosity, compatibility, in vitro drug release, antibacterial activity, cytotoxicity, and stability. The results showed that the size, PDI, and zeta potential of optimized CHX-NPs were 53.07±10.17 nm, 0.36±0.02, and 27.63±4.16 mV, respectively. Moreover, the optimized ISGF loading CHX-NPs showed a gelling temperature at 34.3±1.2°C within 120.00±17.32 s with a pH value of 4.06. The viscosity of the formulations at 4°C was 54.33±0.99 cP. The DSC and FTIR showed no interaction between ingredients. The optimal formulations showed a prolonged release of up to 7 days while providing potential antibacterial activity and were safe for normal gingival fibroblast cells. Moreover, the formulations had high stability at 4°C and 25°C for 3 months. In conclusion, the study achieved the successful development of ISGF loading CHX-NPs formulations for effectiveness use in periodontal treatment.