Voriconazole Eye Drops: Enhanced Solubility and Stability through Ternary Voriconazole/Sulfobutyl Ether ß-Cyclodextrin/Polyvinyl Alcohol Complexes.

Voriconazole (VCZ) is a broad-spectrum antifungal agent used to treat ocular fungal keratitis. However, VCZ has low aqueous solubility and chemical instability in aqueous solutions. This study aimed to develop VCZ eye drop formulations using cyclodextrin (CD) and water-soluble polymers, forming CD complex aggregates to improve the aqueous solubility and chemical stability of VCZ. The VCZ solubility was greatly enhanced using sulfobutyl ether ß-cyclodextrin (SBEßCD). The addition of polyvinyl alcohol (PVA) showed a synergistic effect on VCZ/SBEßCD solubilization and a stabilization effect on the VCZ/SBEßCD complex. The formation of binary VCZ/SBEßCD and ternary VCZ/SBEßCD/PVA complexes was confirmed by spectroscopic techniques and in silico studies. The 0.5% w/v VCZ eye drop formulations were developed consisting of 6% w/v SBEßCD and different types and concentrations of PVA. The VCZ/SBEßCD systems containing high-molecular-weight PVA prepared under freeze-thaw conditions (PVA-H hydrogel) provided high mucoadhesion, sustained release, good ex vivo permeability through the porcine cornea and no sign of irritation. Additionally, PVA-H hydrogel was effective against the filamentous fungi tested. The stability study revealed that our VCZ eye drops provide a shelf-life of more than 2.5 years at room temperature, while a shelf-life of only 3.5 months was observed for the extemporaneous Vfend® eye drops.

Structural Characterization Study of a Lipid Nanocapsule Formulation Intended for Drug Delivery Applications Using Small-Angle Scattering Techniques.

Lipid nanocapsules (LNCs) are increasingly being used for various drug delivery applications due to their versatile nature and ability to carry a wide variety of therapeutic drug molecules. In the present investigation, small-angle X-ray (SAXS) and neutron scattering (SANS) techniques were used to elucidate the structure of LNCs. Overall, size measurements obtained from SAXS and SANS techniques were complemented with dynamic light scattering, zeta potential, and cryogenic transmission electron microscopy measurements. The structural aspects of LNCs can be affected by drug loading and the properties of the drug. Here, the impact of drug loading on the overall structure was evaluated using DF003 as a model drug molecule. LNCs with varying compositions were prepared using a phase inversion method. Combined analysis of SAXS and SANS measurements indicated the presence of a core-shell structure in the LNCs. Further, the drug loading did not alter the overall core-shell structure of the LNCs. SANS data revealed that the core size remained unchanged with a radius of 20.0 ± 0.9 nm for unloaded LNCs and 20.2 ± 0.6 nm for drug-loaded LNCs. Furthermore, interestingly, the shell becomes thicker in an order of ∼1 nm in presence of the drug compared to the shell thickness of unloaded LNCs as demonstrated by SAXS data. This can be correlated with the strong association of hydrophilic DF003 with Kolliphor HS 15, a polyethylene glycol-based surfactant that predominantly makes up the shell, resulting in a drug-rich hydrated shell.

Development of Fenofibrate/Randomly Methylated ß-Cyclodextrin-Loaded Eudragit® RL 100 Nanoparticles for Ocular Delivery.

Fenofibrate (FE) has been shown to markedly reduce the progression of diabetic retinopathy and age-related macular degeneration in clinical trials and animal models. Owing to the limited aqueous solubility of FE, it may hamper ocular bioavailability and result in low efficiency to treat such diseases. To enhance the solubility of FE, water-soluble FE/cyclodextrin (CD) complex formation was determined by a phase-solubility technique. Randomly methylated-ß-CD (RMßCD) exhibited the best solubility and the highest complexation efficiency (CE) for FE. Additionally, water-soluble polymers (i.e., hydroxypropyl methyl cellulose and polyvinyl alcohol [PVA]) enhanced the solubility of FE/RMßCD complexes. Solid- and solution-state characterizations were performed to elucidate and confirm the formation of inclusion FE/RMßCD complex. FE-loaded Eudragit® nanoparticle (EuNP) dispersions and suspensions were developed. The physicochemical properties (i.e., pH, osmolality, viscosity, particle size, size distribution, and zeta potential) were within acceptable ranges. Moreover, in vitro mucoadhesion, in vitro release, and in vitro permeation studies revealed that the FE-loaded EuNP eye drop suspensions had excellent mucoadhesive properties and sustained FE release. The hemolytic activity, hen's egg test on chorioallantoic membrane assay, and in vitro cytotoxicity test showed that the FE formulations had low hemolytic activity, were cytocompatible, and were moderately irritable to the eyes. In conclusion, PVA-stabilized FE/RMßCD-loaded EuNP eye drop suspensions were successfully developed, warranting further in vivo testing.

Effect of Soluplus® on γ-cyclodextrin solubilization of irbesartan and candesartan and their nanoaggregates formation.

The poor aqueous solubility of irbesartan (IRB) and candesartan cilexetil (CAC) may hamper their bioavailability when orally or topically administered. Among several attempts, the promising nanoaggregate formation by γ-cyclodextrin (γCD) complexation of drugs in aqueous solution with or without water-soluble polymers was investigated. According to phase solubility studies, Soluplus® showed the highest complexation efficiency (CE) of drug/γCD complexes among the polymers tested. The aqueous solubility of IRB and CAC was markedly increased as a function of Soluplus® concentrations. The binary drug/γCD and ternary drug/γCD/Soluplus® complex formations were supported and confirmed by solid-state characterizations, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FT-IR) spectroscopy. The true inclusion mode was also proved by proton nuclear magnetic resonance (1H-NMR) spectroscopy. The nanoaggregate size and morphology of binary and ternary systems were observed using dynamic light scattering (DLS), and transmission electron microscopy (TEM) techniques. The size of these nanocarriers depends on the concentration of Soluplus®. The use of Soluplus® could significantly enhance drug solubility and stabilize complex nanoaggregates, which could be a prospective platform for drug delivery systems.

Cytotoxicity of ß-Cyclodextrins in Retinal Explants for Intravitreal Drug Formulations.

Cyclodextrins (CDs) have been widely used as pharmaceutical excipients for formulation purposes for different delivery systems. Recent studies have shown that CDs are able to form complexes with a variety of biomolecules, such as cholesterol. This has subsequently paved the way for the possibility of using CDs as drugs in certain retinal diseases, such as Stargardt disease and retinal artery occlusion, where CDs could absorb cholesterol lumps. However, studies on the retinal toxicity of CDs are limited. The purpose of this study was to examine the retinal toxicity of different beta-(ß)CD derivatives and their localization within retinal tissues. To this end, we performed cytotoxicity studies with two different CDs-2-hydroxypropyl-ßCD (HPßCD) and randomly methylated ß-cyclodextrin (RMßCD)-using wild-type mouse retinal explants, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and fluorescence microscopy. RMßCD was found to be more toxic to retinal explants when compared to HPßCD, which the retina can safely tolerate at levels as high as 10 mM. Additionally, studies conducted with fluorescent forms of the same CDs showed that both CDs can penetrate deep into the inner nuclear layer of the retina, with some uptake by Müller cells. These results suggest that HPßCD is a safer option than RMßCD for retinal drug delivery and may advance the use of CDs in the development of drugs designed for intravitreal administration.

Characterization and Evaluation of Ternary Complexes of Ascorbic Acid with γ-Cyclodextrin and Poly(vinyl Alcohol).

Ascorbic acid (AA) is a general antioxidant used in aqueous pharmaceutical formulations. However, in aqueous solutions, AA is unstable and easily oxidized when exposed to air, light and/or heat. Cyclodextrins are well known for their ability to form inclusion complexes with various compounds to improve their solubility and stability. Previous studies demonstrate that cyclodextrins preserve the antioxidant capacity of AA but data for γ-cyclodextrin (γCD) have not been reported. Poly(vinyl alcohol) (PVA) is a hydrophilic polymer widely used as a drug matrix in various pharmaceutical fields, but its application for drug stabilization is limited. This study aimed to investigate the protective ability of γCD on AA through the formation of ternary complexes with PVA. Binary (i.e., AA/γCD, AA/PVA and γCD/PVA) and ternary (i.e., AA/γCD/PVA) complexes were first confirmed. It was reported that those complexes were formed through interactions between the heterocyclic ring of AA, hydroxyl group of PVA and hydrophobic cavity of γCD. The hydrodynamic diameter of complexes was then studied. It was found that the diameter of γCD/PVA complexes increased with respect to the concentration of γCD. Higher γCD concentrations also resulted in increasing hydrodynamic diameters of the ternary complex. The presence of AA in ternary complexes interfered with the aggregation tendency of γCD/PVA binary complexes. Furthermore, the antioxidant capacity of AA in binary and ternary complexes was investigated. It was found that the presence of γCD preserved the antioxidant activity of AA, whereas PVA showed a contrasting effect. The influence of γCD and PVA concentration on antioxidant capacity was then studied through central composite design (CCD). Even though the concentration of γCD significantly affected the inhibition efficiency of the ternary complex, the insignificant influence of PVA could not be ignored. A promising protective ternary complex should consist of an optimized concentration of PVA and a high concentration of γCD.

Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers.

PURPOSE: This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg. METHODS: Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured. RESULTS: The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02-p < 0.001). Heat pain threshold showed no statistical difference. CONCLUSIONS: A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose. TRIAL REGISTRATION: clinicaltrials.gov : NCT02307721.

Solubility of Cyclodextrins and Drug/Cyclodextrin Complexes.

Cyclodextrins (CDs), a group of oligosaccharides formed by glucose units bound together in a ring, show a promising ability to form complexes with drug molecules and improve their physicochemical properties without molecular modifications. The stoichiometry of drug/CD complexes is most frequently 1:1. However, natural CDs have a tendency to self-assemble and form aggregates in aqueous media. CD aggregation can limit their solubility. Through derivative formation, it is possible to enhance their solubility and complexation capacity, but this depends on the type of substituent and degree of substitution. Formation of water-soluble drug/CD complexes can increase drug permeation through biological membranes. To maximize drug permeation the amount of added CD into pharmaceutical preparation has to be optimized. However, solubility of CDs, especially that of natural CDs, is affected by the complex formation. The presence of pharmaceutical excipients, such as water-soluble polymers, preservatives, and surfactants, can influence the solubilizing abilities of CDs, but this depends on the excipients' physicochemical properties. The competitive CD complexation of drugs and excipients has to be considered during formulation studies.

Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane.

According to the Biopharmaceutics Classification System, oral bioavailability of drugs is determined by their aqueous solubility and the ability of the dissolved drug molecules to permeate lipophilic biological membranes. Similarly topical bioavailability of ophthalmic drugs is determined by their solubility in the aqueous tear fluid and their ability to permeate the lipophilic cornea. Enabling pharmaceutical excipients such as cyclodextrins can have profound effect on the drug bioavailability. However, to fully appreciate such enabling excipients, the relationship between their effects and the physicochemical properties of the permeating drug needs to be known. In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated using cellophane and fused cellulose-octanol membranes in a conventional Franz diffusion cell system. The flux (J), the flux ratio (JR) and the apparent permeability coefficients (Papp) demonstrate that γCD increases drug permeability. However, its efficacy depends on the drug properties. Addition of γCD increased Papp of HC (unionized) and IBS (partially ionized) through the dual membrane but decreased the Papp of TEL (fully ionized) that displays low complexation efficacy. The dual cellophane-octanol membrane system was simple to use and gave reproducible results.

Free fatty acid suppositories are as effective as docusate sodium and sorbitol enemas in treating constipation in children.

AIM: A well-documented, clinically proven per rectum treatment for childhood constipation is needed. This phase two clinical trial evaluated the efficacy of suppositories containing free fatty acids (FFA) compared with Klyx docusate sodium and sorbitol enemas. METHODS: A randomised, controlled, single-blind study was undertaken on 77 children aged between one and 17 who presented to an emergency department in Iceland and were diagnosed with constipation. In stage one, 23 patients were randomised to receive lower dose FFA suppositories or Klyx (n = 33). In stage two, 21 different patients were randomised to receive higher dose suppositories and compared with the same Klyx control subjects. RESULTS: The suppositories were effective at bowel emptying in 39% of the group who received the lower FFA doses and 81% of the group receiving higher doses, compared with 88% in the Klyx control group. Symptom relief was obtained in 30% of the group receiving the lower doses and 71% of the group receiving the higher doses, compared with 73% in the control group. CONCLUSION: The higher dose FFA suppositories were as effective as the Klyx enemas with regard to bowel emptying and symptom relief and might provide an important and less invasive alternative for childhood constipation.

Topical Formulation Comprising Fatty Acid Extract from Cod Liver Oil: Development, Evaluation and Stability Studies.

The purpose of this study was to develop a pharmaceutical formulation containing fatty acid extract rich in free omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid for topical use. Although the health benefits of cod liver oil and other fish oils taken orally as a dietary supplement have been acknowledged and exploited, it is clear that their use can be extended further to cover their antibacterial properties. In vitro evaluation showed that 20% (v/v) fatty acid extract exhibits good activity against strains of the Gram-positive bacteria Staphylococcus aureus, Enterococcus faecalis, Streptoccoccus pyogenes and Streptoccoccus pneumonia. Therefore, free polyunsaturated fatty acids from cod liver oil or other fish oils can be used as safe and natural antibacterial agents. In this study, ointment compositions containing free fatty acids as active antibacterial agents were prepared by using various natural waxes and characterized. The effects of different waxes, such as carnauba wax, ozokerite wax, laurel wax, beeswax, rice bran wax, candelilla wax and microcrystalline wax, in the concentration range of 1% to 5% (w/w) on the ointment texture, consistency and stability were evaluated. The results showed significant variations in texture, sensory and rheological profiles. This was attributed to the wax's nature and chain composition. Microcrystalline wax gave the best results but laurel wax, beeswax and rice bran wax exhibited excellent texturing, similar sensory profiles and well-balanced rheological properties.

Cyclodextrin-poloxamer aggregates as nanocarriers in eye drop formulations: dexamethasone and amphotericin B.

In this present study cyclodextrin (CD)-poloxamer aggregates were characterized and developed as ophthalmic drug carriers. The combined effect of γCD/2-hydroxypropyl-γCD (HPγCD) mixtures and poloxamer on solubilization and permeability of two model drugs, dexamethasone (Dex) and amphotericin B (AmB), was investigated. The CD-poloxamer interaction and complex aggregation were examined by (1)H nuclear magnetic resonance ((1)H-NMR), their solubilizing ability by high-performance liquid chromatography, and their particle size determined by dynamic light scattering and transmission electron microscopy. Formulations containing either 1.5% w/v Dex or 0.15% w/v AmB in eye drop suspensions containing various γCD/HPγCD ratios and poloxamer 407 (P407) were prepared. The solubility of the drugs, surface tension and hemolytic effect of the eye drops and drug permeation from selected formulations were determined. The (1)H-NMR study showed that P407 formed inclusion complex with CDs by inserting its poly(propylene oxide) segment into the CD cavity. P407 and γCD interacted with each other to form nanosized aggregates, and the observed concentration of dissolved γCD and P407 progressively decreased with increasing γCD and P407 concentrations. Including a high proportion of HPγCD improved the drug solubilization and reduced the hemolytic effect. The surface tension of the formulations decreased with increasing P407 concentration. Furthermore, increasing P407 content in the formulations enhanced formation of complex aggregates with consequent slower drug release. It was concluded that the drug/γCD/HPγCD complex was stabilized by P407 through formation of multi-component aggregates. Thus, CD-poloxamer aggregates are self-assembled nanocarriers from which drug delivery characteristics can be adjusted by changing the γCD/HPγCD/P407 ratios.

Development of eye drops containing antihypertensive drugs: formulation of aqueous irbesartan/γCD eye drops.

Aqueous nanoparticulated eye drop formulations based on γ-cyclodextrin (γCD) complexes were developed and tested in vitro. Three antihypertensive drugs, i.e. enalapril maleate, irbesartan and verapamil HCl, that have been shown to possess IOP-lowering activity were selected for this study. All three drugs displayed Bs-type phase-solubility diagrams in aqueous γCD solutions and had relatively low affinity for γCD. Irbesartan was selected for further formulation development. The drug was relatively stable at pH 4.5 but somewhat less stable at physiologic pH. However, presence of γCD in the aqueous media enhanced the chemical stability of irbesartan. Aqueous γCD-based eye drop formulations containing 1% and 2% (w/v) irbesartan were prepared and the effect of pH on the particles size distribution and drug release investigated. Only ∼2% of the drug was in solution in the pH 4.5 formulations but up to 45% in the pH 7 formulations. The pH 7 formulations, where larger fraction of the drug was in solution, displayed somewhat greater drug permeation flux but much lower drug permeation coefficients than the pH 4.5 formulations. Dynamic light scattering studies indicated the faster permeation was due to formation of smaller particles in presence tyloxapol.

Drug-like properties of tyrosine kinase inhibitors in ophthalmology: Formulation and topical availability.

Tyrosine kinase inhibitors (TKIs) can inhibit edema and neovascularization, such as in age-related macular degeneration and diabetic retinopathy. However, their topical administration in ophthalmology is limited by their toxicity and poor aqueous solubility. There are multiple types of TKIs, and each TKI has an affinity to more than one type of receptor. Studies have shown that ocular toxicity can be addressed by selecting TKIs that have a high affinity for specific vascular endothelial growth factor receptors (VEGFRs) but a low affinity for epidermal growth factor receptors (EGFRs). Drugs permeate from the aqueous tear fluid into the eye via passive diffusion. Thus, a sustained high concentration of the dissolved drug in the aqueous tear fluid is essential for a successful delivery to posterior tissues such as the retina. Unfortunately, the aqueous solubility of the TKIs that have the most favorable VEGFR/EGFR affinity ratio, that is, axitinib and cabozantinib, is well below 1 µg/mL, making their topical delivery very challenging. This is a review of the drug-like properties of TKIs that are currently being evaluated or have been evaluated as ophthalmic drugs. These properties include their solubilization, cyclodextrin complexation, and ability to permeate from the aqueous tear fluid to the posterior eye segment.

New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration.

Retinitis pigmentosa (RP) is a form of retinal degeneration affecting a young population with an unmet medical need. Photoreceptor degeneration has been associated with increased guanosine 3',5'-cyclic monophosphate (cGMP), which reaches toxic levels for photoreceptors. Therefore, inhibitory cGMP analogues attract interest for RP treatments. Here we present the synthesis of dithio-CN03, a phosphorodithioate analogue of cGMP, prepared using the H-phosphonothioate route. Two crystal modifications were identified as a trihydrate and a tetrahydrofuran monosolvates. Dithio-CN03 featured a lower aqueous solubility than its RP-phosphorothioate counterpart CN03, a drug candidate, and this characteristic might be favorable for sustained-release formulations aimed at retinal delivery. Dithio-CN03 was tested in vitro for its neuroprotective effects in photoreceptor models of RP. The comparison of dithio-CN03 to CN03 and its diastereomer SP-CN03, and to their phosphate derivative oxo-CN03 identifies dithio-CN03 as the compound with the highest efficacy in neuroprotection and thus as a promising new candidate for the treatment of RP.

Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions.

Cyclodextrins (CDs) are cyclic oligosaccharides that emerged as industrial excipients in the early 1970s and are currently found in at least 130 marketed pharmaceutical products, in addition to numerous other consumer products. Although CDs have been the subject of close to 100,000 publications since their discovery, and although their structure and properties appear to be trivial, CDs are constantly surprising investigators by their unique physicochemical properties. In aqueous solutions, CDs are solubilizing complexing agents of poorly soluble drugs while they can also act as organic cosolvents like ethanol. CDs and their complexes self-assemble in aqueous solutions to form both nano- and microparticles. The nanoparticles have diameters that are well below the wavelength of visible light; thus, the solutions appear to be clear. However, the nanoparticles can result in erroneous conclusions and misinterpretations of experimental results. CDs can act as penetration enhancers, increasing drug permeation through lipophilic membranes, but they do so without affecting the membrane barrier. This review is an account of some of the unexpected results the authors have encountered during their studies of CDs as pharmaceutical excipients.

Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations.

In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA-H) and salts of sodium (-Na), calcium (-Ca), ammonium (-NH4 ), triethylammonium (-TEA), tris(hydroxymethyl)aminomethane (-Tris), benethamine (-Bnet), and benzathine (-BZ) were prepared. Their solid-state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2 O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X-ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA-BZ featured the lowest aqueous solubility and hygroscopicity, with 50 µg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X-ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP - conformation at the phosphorus atom.

Celecoxib/Cyclodextrin Eye Drop Microsuspensions: Evaluation of In Vitro Cytotoxicity and Anti-VEGF Efficacy for Retinal Diseases.

Celecoxib (CCB), a cyclooxygenase-2 inhibitor, is capable of reducing oxidative stress and vascular endothelial growth factor (VEGF) expression in retinal cells and has been shown to be effective in the treatment of diabetic retinopathy and age-related macular degeneration. However, the ocular bioavailability of CCB is hampered due to its very low aqueous solubility. In a previous study, we developed 0.5% (w/v) aqueous CCB eye drop microsuspensions (MS) containing randomly methylated ß-cyclodextrin (RMßCD) or γ-cyclodextrin (γCD) and hyaluronic acid (HA) as ternary CCB/CD/HA nanoaggregates. Both formulations exhibited good physicochemical properties. Therefore, we further investigated their cytotoxicity and efficacy in a human retina cell line in this study. At a CCB concentration of 1000 µg/mL, both CCB/RMßCD and CCB/γCD eye drop MS showed low hemolysis activity (11.1 ± 0.3% or 4.9 ± 0.2%, respectively). They revealed no signs of causing irritation and were nontoxic to retinal pigment epithelial cells. Moreover, the CCB eye drop MS exhibited significant anti-VEGF activity by reducing VEGF mRNA and protein levels compared to CCB suspended in phosphate buffer saline. The ex vivo transscleral diffusion demonstrated that a high quantity of CCB (112.47 ± 37.27 µg/mL) from CCB/γCD eye drop MS was deposited in the porcine sclera. Our new findings suggest that CCB/CD eye drop MS could be safely delivered to the ocular tissues and demonstrate promising eye drop formulations for retinal disease treatment.

A promising synthetic citric crosslinked ß-cyclodextrin derivative for antifungal drugs: Solubilization, cytotoxicity, and antifungal activity.

Effective antifungal therapy for the treatment of fungal keratitis requires a high drug concentration at the corneal surface. However, the use of natural ß-cyclodextrin (ßCD) in the preparation of aqueous eye drop formulations for treating fungal keratitis is limited by its low aqueous solubility. Here, we synthesized water-soluble anionic ßCD derivatives capable of forming water-soluble complexes and evaluated the solubility, cytotoxicity, and antifungal efficacy of drug prepared using the ßCD derivative. To achieve this, a citric acid crosslinked ßCD (polyCTR-ßCD) was successfully synthesized, and the aqueous solubilities of selected antifungal drugs, including voriconazole, miconazole (MCZ), itraconazole, and amphotericin B, in polyCTR-ßCD and analogous ßCD solutions were evaluated. Among the drugs tested, complexation of MCZ with polyCTR-ßCD (MCZ/polyCTR-ßCD) increased MCZ aqueous solubility by 95-fold compared with that of MCZ/ßCD. The inclusion complex formation of MCZ/ßCD and MCZ/polyCTR-ßCD was confirmed by spectroscopic techniques. Additionally, the nanoaggregates of saturated MCZ/polyCTR-ßCD and MCZ/ßCD solutions were observed using dynamic light scattering and transmission electron microscopy. Moreover, MCZ/polyCTR-ßCD solution exhibited good mucoadhesion, sustained drug release, and high drug permeation of porcine cornea ex vivo. Hen's Egg test-chorioallantoic membrane assay and cell viability study using Statens Seruminstitut Rabbit Cornea cell line showed that both MCZ/polyCTR-ßCD and MCZ/ßCD exhibited no sign of irritation and non-toxic to cell line. Additionally, antifungal activity evaluation demonstrated that all isolated fungi, including Candida albicans, Aspergillus flavus, and Fusarium solani, were susceptible to MCZ/polyCTR-ßCD. Overall, the results showed that polyCTR-ßCD could be a promising nanocarrier for the ocular delivery of MCZ.

Clinical trial: marine lipid suppositories as laxatives.

UNLABELLED: Cod-liver oil and other marine products containing polyunsaturated fatty acids have anti-inflammatory, anti-bacterial and anti-viral effects and may be useful in the treatment of various inflammatory and infectious diseases. We developed suppositories and ointment with 30% free fatty acid (FFA) extract from omega-3 fish oil. Our purpose was to evaluate the safety of marine lipid suppositories and ointment in healthy volunteers and to explore the laxative effect of the suppositories. Thirty healthy volunteers were randomized either to a study group administrating 30% FFA suppositories and applying 30% FFA ointment to the perianal region twice per day for two weeks, or to a control group using placebo suppositories and ointment in a double blinded manner. RESULTS: No serious toxic effects or irritation were observed. In the study group 93% felt the urge to defecate after administration of the suppositories as compared to 37% in the control group (P = 0.001). Subsequently 90% in the study group defecated, compared to 33% in the control group (P = 0.001). CONCLUSION: The marine lipid suppositories and ointment were well tolerated with no significant toxic side effects observed during the study period. The suppositories have a distinct laxative effect and we aim to explore this effect in further clinical trials.