Controlled Release Formulations Research Articles

The Present Difficulties and Potential Benefits of Dopaminergic Agents in Parkinson's Disease Treatment

Parkinson's disease (PD) is a progressive neurological condition characterized by bradykinesia, rigidity, tremors, and impaired balance, among other motor impairments. The issue arises from dopaminergic neurons located in the spinal column of the brain. This research report examines the therapeutic potential of dopaminergic medications in the management of Parkinson's disease. The central concept of Parkinson's disease (PD) revolves around the notion that dopaminergic pathways exert significant influence over the regulation of movement. The book examines various dopaminergic medications, elucidating their mechanisms of action and the impact they exert on dopamine signaling. Examples of these medications include levodopa, dopamine agonists, and monoamine oxidase-B (MAO-B) inhibitors. Although dopaminergic medicines initially aid in the treatment of Parkinson's disease (PD), prolonged usage of these medications gives rise to several complications. Experiencing dyskinesias and motor fluctuations, characterized by episodes of involuntary movements and behaviors that are undesired, is a significant challenge. This study investigates the underlying causes of these difficulties and explores potential treatment options, including the use of controlled-release formulations and further therapy. The book discusses the non-motor symptoms of Parkinson's disease (PD), as well as the use of dopaminergic medications to treat mood disorders, autonomic dysfunction, and cognitive loss. Dopaminergic medications remain crucial in reducing motor symptoms and enhancing the quality of life for those with Parkinson's disease. Parkinson's disease (PD) is a complex condition with multiple distinct variations. In order to address its existing challenges and explore its potential implications for future Parkinson's disease medications, a comprehensive and effectively coordinated strategy is required.

Preparation of pH-Responsive Kas@ZnO Quantum Dots for Synergistic Control of Rice Blast and Enhanced Disease Resistance in Rice.

The construction of controlled-release formulations improves the sustained-release performance and utilization efficiency of pesticides, which are important aspects in plant protection and environmental chemistry. The current study employs kasugamycin (Kas), which is widely used to control Magnaporthe oryzae, conjugated with carboxyl-functionalized ZnO quantum dots via amide linkages to yield a pH-responsive pesticide delivery system (Kas@ZnO). Physicochemical characterizations indicated the successful preparation of the Kas@ZnO nanoparticles. In vitro drug release assessments indicated that Kas@ZnO exhibited a loading capacity of 21.05% and could effect the controlled release of Kas in an acidic environment, which is beneficial given the unique acidic microenvironment of M. oryzae. Bioactivity assays demonstrated that Kas@ZnO could simultaneously inhibit mycelial growth and spore germination. Additionally, bioactivity tests showed that the control efficacy of Kas@ZnO against rice blast reached 67.43% after 14 days of in vivo spray inoculation, which was higher than that obtained with Kas (55.50%), suggesting improved beneficial effects of Kas@ZnO application over a prolonged duration. Moreover, Kas@ZnO enhanced the activity of defense-related enzymes in rice and upregulated the expression of defense-related genes, such as OsPR2, OsPR3, OsPR5, OsWRKY45, OsLYP6, and OsNAC4. Ultimately, the biosafety assessments revealed that Kas@ZnO did not exert any harmful effects on rice and demonstrated slight toxicity toward zebrafish. These findings indicate that Kas@ZnO can function as a pH-sensitive pesticide delivery system, allowing for targeted release of the pesticide within plant tissues. This technology demonstrates significant potential for eco-friendly plant disease management.

A Review on Nanotechnological Approaches for the Management of Stored Insect-Pests: Present Scenario and Future Prospects

Approximately 10% to 30% of the stored agricultural produce is damaged out of which 26% is due to insect-pest infestation thus seriously impacting the food security. The infestation also leads to loss of quality and thereby affecting the overall profitability. In absence of enough storage space, usually farmers dispose-off their produce immediately after harvest and thus do not get remunerative prices. For those opting for storage, physical and chemical methods are in vogue to manage the storage insect-pests. Fumigation with chemical pesticides such as methyl bromide and aluminium phosphide is a common method, though it has its own health and environmental risks. Inhalation of phosphine gas released when aluminium phosphide is used could seriously affect human animal health, sometimes leading to deaths. Thus for using these fumigants, strict supervision of government recognized experts is required. Due to their wide usage, some insect-pests have developed resistance against these molecules. Nanotechnology has created numerous new opportunities in agriculture and allied sectors. Insecticide formulations based on nanotechnology could be a viable alternative to toxic chemicals like aluminium phosphide to manage storage insect-pests. In recent years, a variety of formulations including solid nanopesticides, controlled-release formulations, nano-emulsions, and nano-suspensions have been developed possessing different modes of actions and applications. Their small size is a significant advantage because it provides higher insect-body surface area coverage and thus enhanced efficacy as compared to traditional pesticides. Aside from their small size, they are reported to be safe for non-target beneficial organisms. Nano-pesticides can thus prove as effective and eco-friendly alternatives for insect pest control in storage. However, there is a need to establish their safety on the human and animal ecosystems to rule out their ecological hazards over time. In absence of such information, nanopesticides will not be widely accepted despite their other beneficial effects. In this article, an effort is made to review the current status of nano-formulations for the management of storage-insect-pests, the research and extension gaps and ways to bridge the gaps to ensure safe use of the technology for efficient management of postharvest storage losses.

Applications of different forms of nitrogen fertilizers affect soil bacterial community but not core ARGs profile.

The objective of this study was to investigate the impact of various chemical nitrogen fertilizers on the profile of antibiotic resistance genes (ARGs) in soil. A microcosm experiment was conducted with four treatments, including CK (control with no nitrogen), AN (ammonium nitrogen), NN (nitrate nitrogen), and ON (urea nitrogen), and the abundance of ARGs was assessed over a 30-day period using a metagenomic sequencing approach. The levels of core ARGs varied between 0.16 and 0.22 copies per cell across different treatments over time. The abundance of core ARGs in the ON treatment closely resembled that of the CK treatment, suggesting that environmentally friendly nitrogen fertilizers, particularly those in controlled release formulations, may be preferable. The core ARG abundance in the AN and NN treatments exhibited noticeable fluctuations over time. Overall, chemical nitrogen fertilizers had minimal effects on the core ARG profile as determined by principal component analysis and clustering analyses. Conversely, distinct and significant changes in bacterial communities were observed with the use of different nitrogen fertilizers. However, the influence of nitrogen fertilizers on the core ARGs is limited due to the unaffected potential bacterial hosts. Nitrogen-cycling-related genes (NCRGs), such as those involved in nitrogen-fixing (nifK, nifD, nifH) and denitrification (narG, napA, nirK, norB, nosZ) processes, exhibit a positive correlation with ARGs (rosA, mexF, bacA, vanS), indicating a potential risk of ARG proliferation during intense denitrification activities. This study indicates that the application of chemical nitrogen has a minimal effect on the abundance of ARGs in soil, thereby alleviating concerns regarding the potential accumulation of ARGs due to the use of chemical nitrogen fertilizers.

Impact of sink conditions on drug release behavior of controlled-release formulations

Developing a controlled release (CR) formulations is a complex and iterative process, often requiring preclinical or clinical studies to establish in vitro-in vivo correlations. This can be particularly challenging for poorly soluble drugs due to the non-sink conditions encountered in vitro. Although compendial dissolution methods (e.g., USP II, IV) have historically been used to understand the dissolution performance of CR formulations, there is increasing interest in more physiologically relevant experimental techniques to improve the predictive ability. In this study, traditional USP apparatus as well as the biorelevant absorptive dissolution apparatus were employed to understand the impact of apparatus type and sink condition on the release mechanisms of CR formulations and in turn evaluate the application of absorptive dissolution apparatus for dissolution testing of CR formulations. Release mechanisms were further analyzed using the Peppas equations, providing additional mechanistic insights. The release behavior showed a strong dependence on sink conditions for drugs with low intrinsic solubility, while highly soluble drugs were unaffected by dissolution conditions. Interestingly, the dissolution mechanism was found to be independent of the apparatus type. The study clearly underscores the importance of considering the sink conditions in developing more predictive and biorelevant dissolution testing methods for CR formulations. Furthermore, the study highlights the potential impact on the sink and resultant differences in the drug release mechanisms as a function of the dose.

Unlocking The Potential Of Natural Polymers: A Comparative Study For Innovative Drug Delivery Systems

This study aims to characterize and compare four biopolymers - pectin, guar gum, xanthan gum, and sodium alginate - for their potential use in drug delivery systems by evaluating their hydrophilicity, pH sensitivity, and thermosensitivity. Biopolymer films were prepared and subjected to water absorption tests for hydrophilicity, gravimetric analysis in varying pH conditions for pH sensitivity, and weight change measurements after heat exposure for thermosensitivity. Each test was conducted in five trials to ensure reliability. Pectin demonstrated the highest responsiveness across all tests, showing rapid water absorption (6.46 seconds), significant pH sensitivity (0.53g weight change in acidic conditions), and high thermosensitivity (0.378g weight change). Guar gum showed moderate responsiveness, while xanthan gum and sodium alginate exhibited the most stability across varying conditions. Pectin's high responsiveness suggests suitability for smart, multi-stimuli-responsive systems. Guar gum's moderate responsiveness indicates potential for controlled release formulations. The stability of xanthan gum and sodium alginate makes them ideal for applications requiring consistent drug release in diverse physiological environments. This study offers a comprehensive, comparative analysis of four widely used biopolymers, filling a gap in the existing literature. The results provide a foundation for developing tailored, sustainable drug delivery systems, contributing to the advancement of personalized medicine and environmentally friendly pharmaceutical practices

Integrated Pest Management: An Update on the Sustainability Approach to Crop Protection.

Integrated Pest Management (IPM) emerged as a pest control framework promoting sustainable intensification of agriculture, by adopting a combined strategy to reduce reliance on chemical pesticides while improving crop productivity and ecosystem health. This critical review synthesizes the most recent advances in IPM research and practice, mostly focusing on studies published within the past five years. The Review discusses the key components of IPM, including cultural practices, biological control, genetic pest control, and targeted pesticide application, with a particular emphasis on the significant advancements made in biological control and targeted pesticide delivery systems. Recent findings highlight the growing importance of genetic control and conservation biological control, which involves the management of agricultural landscapes to promote natural enemy populations. Furthermore, the recent discovery of novel biopesticides, including microbial agents and plant-derived compounds, has expanded the arsenal of tools available for eco-friendly pest management. Substantial progress has recently also been made in the development of targeted pesticide delivery systems, such as nanoemulsions and controlled-release formulations, which can minimize the environmental impact of pesticides while maintaining their efficacy. The Review also analyzes the environmental, economic, and social dimensions of IPM adoption, showcasing its potential to promote biodiversity conservation and ensure food safety. Case studies from various agroecological contexts demonstrate the successful implementation of IPM programs, highlighting the importance of participatory approaches and effective knowledge exchange among stakeholders. The Review also identifies the main challenges and opportunities for the widespread adoption of IPM, including the need for transdisciplinary research, capacity building, and policy support. In conclusion, this critical review discusses the essential role of IPM components in achieving the sustainable intensification of agriculture, as it seeks to optimize crop production while minimizing adverse environmental impacts and enhancing the resilience of agricultural systems to global challenges such as climate change and biodiversity loss.

Comparison Study of Aloin-Curcumin Nanoparticles by Taking 2 Different Ratios and Analyses by Using Drug Design Experimental Study.

Numerous chemopreventive drugs like aloin and curcumin have demonstrated potential effects in cancer treatment; however, their efficacy is limited by low bioavailability. Thus, the primary goal of this research was to formulate a unique method by using the herbal drugs synergistically and improve the bioavailability of these anticancer drugs here, using the nanoprecipitation method for two well-active constituents of known natural herbal compounds. Aloin (AL)-curcumin (CUR) were co-loaded into polymeric nanoparticles made of poly (D, L-lactide-co-glycolide) and surfactant-polyvinyl alcohol, with the experiment’s response being evaluated using Stat-Ease software. To create dual-loaded nanoparticles containing aloin and curcumin, using different ratios sand optimizing the best formulation. (60:120). For aloin curcumin, optimize the better formulation with controlled release formulation having less than 100 nm size of particle and drug entrapment was 86.09% while for (60:60) of aloin -curcumin having 99.1 nm particle size of drug and encapsulation efficiency was 72.05%.

Two birds with one stone: Multifunctional controlled‐release formulations of pesticides

AbstractControlled release and nanotechnology techniques hold promising potential for propelling the pesticide industry toward the goals of green revolution. This study introduces the concept of atom economy into the multifunctionality of controlled‐release formulations (CRFs) of pesticides from both economic and sustainable perspectives. In addition to their core function of controlling the release of active ingredient, carriers also provide additional benefits, including enhanced foliar adhesion and pesticide translocation, nutritional function, synergistic bioactivity, safety for nontarget organisms, crop stress alleviation, reduced soil leaching, soil remediation, and fluorescence visualization. These additional functions are highlighted and taken seriously. Through ingenious excogitation, the multifunctional CRFs of pesticides can achieve multiple objectives, enhancing input efficiency while minimizing environmental impacts. We tentatively blazed a trail by reviewing the recent advances in multifunctional CRFs of pesticides from the perspective of green chemistry. Additionally, potential development and implementation barriers of CRFs were discussed, emphasizing the necessity for robust field trials and comprehensive systems‐level efficacy/biosafety evaluations to substantially boost the technical readiness and performance of multifunctional CRFs of pesticides. Our goal is to expand the multifunctional concept for pesticide formulations, thereby accelerating the development of global sustainable agrochemical products.

Recent Advances in Biopesticide Formulations for Targeted Insect Pest Management: A Review

The increasing environmental and health concerns associated with the use of synthetic chemical pesticides have driven the need for alternative, eco-friendly pest management solutions. Biopesticides, derived from natural sources such as plants and microorganisms, offer a promising solution, as they are less toxic, decompose quickly, and target specific pests with minimal impact on non-target organisms. Recent advancements in biopesticide formulations, including nano pesticides, controlled release formulations (CRFs), hydrogels, polymer-coated granules, and tablets, are enhancing the effectiveness, stability, and environmental safety of these products. The integration of nanotechnology and controlled release systems in biopesticides is opening new avenues for sustainable agriculture. This review discusses the various biopesticide formulation technologies, highlighting their advantages, disadvantages, and future prospects.

Analyzing topological descriptors of guar gum and its derivatives for predicting physical properties in carbohydrates

Guar gum is a non-ionic polysaccharide found in abundance in nature. It may be used as a thickening agent, stabilizer, or emulsifier in pharmaceutical formulations, food products, or cosmetics. Its ability to form viscous solutions makes it useful in drug delivery systems, controlled release formulations, and as a matrix for oral drug delivery. The investigation of chemical structures through graph invariants is of great concern. Topological descriptors are numerical numbers associated with the molecular structure and have the ability to predict certain physical and chemical properties of the underlying structure. In this paper, we have calculated the harmonic index, the inverse sum indeg index, the third Zagreb index, the Hyper Zagreb index, the sigma index, the reformulated first Zagreb index, the reformulated multiplicative first Zagreb index, the Harmonic–arithmetic index, and the Atom Bond sum connectivity indices of guar gum and its chemical derivatives. Finally, the chemical applicability of these topological descriptors is checked for different carbohydrates (monosaccharides, disaccharides, and polysaccharides) by using straight-line, parabolic and logarithmic regression models. It has been observed that these topological descriptors are useful to predict two physical properties, namely density and molecular weight.

An Updated Overview of Gastro-retentive Floating Drug Delivery Systems: Formulation Strategies and Application

Gastro-retentive floating drug delivery systems (GRFDDS) have emerged as a significant advancement in enhancing the bioavailability and therapeutic efficacy of various medications. This review article provides a comprehensive overview of recent innovations in GRFDDS, highlighting their formulation strategies, mechanisms of buoyancy, and various applications in drug delivery. The role of various polymeric materials, gas-forming agents, and optimization techniques is discussed which are generally employed to develop effective floating systems. Additionally, keen insight is brought on applications of GRFDDS in treating gastrointestinal disorders, enhancing the pharmacokinetics of drugs with narrow absorption windows, and their potential in controlled-release formulations. In this review, authors compiled the recent reported literatures about the gastro-retentive floating drug delivery systems since 2015 to underline the effectiveness and safety profiles of these systems. This review aims to consolidate current knowledge and inspire future research directions in the development of GRFDDS for improved patient outcomes. Keywords: Floating; Gastro-retentive; drug delivery; HPMC; Effervescent

Controlled release formulations of organophosphorus pesticides based on ecofriendly novel and conventional matrices for agro-environmental sustainability

Controlled release formulations (CRFs) of the organophosphorus pesticides diazinon and dichlorvos were prepared from a novel cow dung ash (CDA) matrix and the more conventional starch (STA) matrix. Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and X-ray diffraction (XRD) were used to characterize the CRFs. FTIR and XRD spectral data provide evidence for pesticide-matrix interactions fundamental to observed matrix surface binding and pesticide release behaviour in water and soil environments. Properties evaluation of the CRFs reveal similar magnitudes of loading capacity and encapsulation efficiency of CDA- and STA-based CRFs of both pesticides, while the order CDA > STA prevails in matrix porosity and swelling ability. Technical grade (TG) and the CRF-encapsulated pesticides exhibit “burst” release profiles in water; pesticide quantities released at similar lengths of time follow the order TG >> STA-CRF > CDA-CRF, thus revealing the capacity of the CRFs to constrain the active ingredients from free mobility, with CDA-CRF being the more slightly efficacious. The Korsmeyer-Peppas equation reasonably models pesticide release from both CRFs into water, giving n values consistent with both water diffusion into the matrix and matrix relaxation as kinetically important in both matrices. Soil column experiments demonstrate the potential of the CFRs to mitigate ground water pollution. Overall, the results show that CDA- and STA-based CRFs of both pesticides have roughly the same potency for pesticide controlled release and ground water pollution mitigation. Deployment of these CFRs can contribute to the drive for agro-environmental sustainability, while the use of CDA, a waste material, as a matrix in controlled pesticide delivery would resonate with sustainable bioresource utilization.

From quarry by-products to a zeolites-based Zn fertilizer with increased resistance to rain leaching

In the face of an extensive literature on the use of zeolites for the removal of metals from water for environmental purposes, it is seldom considered that some metals are also essential nutrients for life and that zeolites could be profitably used to dose their release. Among these, Zn is a key micronutrient, and when its demand by crop is not fully balanced by adequate accessibility, fertilization must be provided using Zn salts that can be, however, easily leached and partly wasted in the environment.In an attempt to solve this critical problem, a new controlled-release formulation of Zn using zeolite-containing geomaterials was designed, prepared, characterized, and tested by applying a sequential, multi-method approach. Different formulations were trialed, and the most effective included 30 wt% pumice by-product and 70 wt% clinoptilolite-rich zeolitized tuff, with about 20 mg/g of exchangeable Zn2+. The enrichment process reached equilibrium after about 8 h, a timing well-tuned with technology transfer. Desorption kinetic tests in a weekly acid environment revealed gradual Zn release, with about 4.28 wt% released after 6 h. When tested as a foliar fertilizer on Vitis vinifera, this formulation demonstrated superior resistance to leaching under simulated rainfall conditions compared to conventional ZnSO4·6H2O fertilizer, maintaining the initial level of Zn (130 mg/kg of dry leaves), while about 22 % of the Zn applied with ZnSO4·6H2O was loss. This outcome was plausibly due to mineral particle adhesion to leaf. Preliminary cost estimates suggest that the product designed here can be placed in the market with competitive sales prices.

Cellulase-responsive hydroxypropyl cellulose-anchored hollow mesoporous silica carriers for pesticide delivery

In this study, a cellulase-responsive controlled-release formulation (FPR-HMS-HPC) was developed by grafting hydroxypropyl cellulose (HPC) onto fipronil (FPR) loaded hollow mesoporous silica (HMS) nanoparticles via ester linkage. The FPR-HMS-HPC formulation was characterized using scanning and transmission electron microscopies, Fourier transform infrared spectroscopy, and thermogravimetric analysis. The results indicated that FPR-HMS-HPC exhibited a high loading capacity of 10.0 % (w/w) and demonstrated favorable responsiveness to cellulase enzyme. Moreover, its insecticidal efficacy against Reticulitermes flaviceps surpassed that of an equivalent dose of FPR. Toxicology studies showed that the mortality and hatching rates of zebrafish exposed to FPR-HMS-HPC nanoparticles were reduced by >6.5 and 8.0 times, respectively. Thus, HPC-anchored HMS nanoparticles as insecticide delivery systems present a sustainable method for pest control significantly reducing harm to non-target organisms and the environment.

Combination Nanomedicine Strategy for Preventing High-Risk Corneal Transplantation Rejection.

High-risk (HR) corneal transplantation presents a formidable challenge, with over 50% of grafts experiencing rejection despite intensive postoperative care involving frequent topical eyedrop administration up to every 2 h, gradually tapering over 6-12 months, and ongoing maintenance dosing. While clinical evidence underscores the potential benefits of inhibiting postoperative angiogenesis, effective antiangiogenesis therapy remains elusive in this context. Here, we engineered controlled-release nanomedicine formulations comprising immunosuppressants (nanoparticles) and antiangiogenesis drugs (nanowafer) and demonstrated that these formulations can prevent HR corneal transplantation rejection for at least 6 months in a clinically relevant rat model. Unlike untreated corneal grafts, which universally faced rejection within 2 weeks postsurgery, a single subconjunctival injection of the long-acting immunosuppressant nanoparticle alone effectively averted graft rejection for 6 months, achieving a graft survival rate of ∼70%. Notably, the combination of an immunosuppressant nanoparticle and an anti-VEGF nanowafer yielded significantly better efficacy with a graft survival rate of >85%. The significantly enhanced efficacy demonstrated that a combination nanomedicine strategy incorporating immunosuppressants and antiangiogenesis drugs can greatly enhance the ocular drug delivery and benefit the outcome of HR corneal transplantation with increased survival rate, ensuring patient compliance and mitigating dosing frequency and toxicity concerns.

Design and characterization of controlled release formulation of Mesna by using different polymers

Design and characterization of controlled release formulation of Mesna by using different polymers

CHITOSAN / HEXAMOLYBDATE NANOSTRUCTURES FOR ORAL DRUG DELIVERY

Background: In recent decades, substantial progress has been achieved in the field of drug delivery through the creation of controlled-release formulations, leading to significant medical advancements. The primary objective of these controlled release systems is to sustain the desired drug concentration in the bloodstream or specific tissues for an extended duration. One class of nanostructures is polyoxometalates (POMs), which are negatively charged anionic nanoclusters consisting of metal and oxygen atoms. POMs are notable for their ability to be precisely controlled in size and shape. These characteristics, combined with their inherent negative charge, contribute to their stability and make them highly versatile structures. Aim: This study aimed to examine the self-assembly of organic-inorganic hybrids using polyoxometalate (POM) Lindqvist-type hexamolybdate and chitosan to synthesize novel 3D nanostructures. These nanostructures were then investigated for their suitability as nanocarriers for the chemotherapy drug )Temozolomide TMZ(. The release of TMZ from the nanocarrier was studied under various pH conditions. Methods: This study comprises two practical components. The first part focuses on synthesizing hierarchical nanostructures designed to load TMZ drugs. The amount of drug loaded onto the as-prepared nanostructure of POM-Chitosan was determined using High-Performance Liquid Chromatography (HPLC) at various loading times. The second part of the study investigates the release process of the TMZ drug from the hierarchical nanostructures. This release process is examined in two buffer solutions with distinct pH values. Results: The surface characteristics, size, chemical composition, and identity of the nanostructures were confirmed using techniques such as HPLC, FTIR, XRD, SEM, and XPS. The results confirm the successful complexation of chitosan with POM Lindqvist-type hexamolybdate. Discussion: The nanocarriers demonstrated an intriguing pH-dependent release behavior, suggesting their potential application in drug delivery systems. Conclusions: In this study, new nanocarriers of chitosan and POM were successfully prepared and loaded with TMZ (21% loading) via self-assembly for oral drug delivery. The as-prepared nanocarrier form of TMZ was fully characterized via XRD, FTIR, XPS, and SEM. The as-prepared oral form of TMZ showed an excellent pH-dependent release of TMZ, where the release rate at pH 7.4 was considerably faster than at pH 2.8.

HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus‑Based In Vivo Prediction in Humans: Part II.

In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VI˃ C-VI˃A-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038µg/ mL and 0.00023µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.

Clinical Ocular Exposure Extrapolation for a Complex Ophthalmic Suspension Using Physiologically Based Pharmacokinetic Modeling and Simulation.

The development of generic ophthalmic drug products with complex formulations is challenging due to the complexity of the ocular system and a lack of sensitive testing to evaluate the interplay of its physiology with ophthalmic drugs. New methods are needed to facilitate the development of ophthalmic generic drug products. Ocular physiologically based pharmacokinetic (O-PBPK) models can provide insight into drug partitioning in eye tissues that are usually not accessible and/or are challenging to sample in humans. This study aims to demonstrate the utility of an ocular PBPK model to predict human exposure following the administration of ophthalmic suspension. Besifloxacin (Bes) suspension is presented as a case study. The O-PBPK model for Bes ophthalmic suspension (Besivance® 0.6%) accounts for nasolacrimal drainage, suspended particle dissolution in the tears, ocular absorption, and distribution in the rabbit eye. A topical controlled release formulation was used to integrate the effect of Durasite® on Bes ocular retention. The model was subsequently used to predict Bes exposure after its topical administration in humans. Drug-specific parameters were used as validated for rabbits. The physiological parameters were adjusted to match human ocular physiology. Simulated human ocular pharmacokinetic profiles were compared with the observed ocular tissue concentration data to assess the OCAT models' ability to predict human ocular exposure. The O-PBPK model simulations adequately described the observed concentrations in the eye tissues following the topical administration of Bes suspension in rabbits. After adjustment of physiological parameters to represent the human eye, the extrapolation of clinical ocular exposure following a single ocular administration of Bes suspension was successful.