Rapidly Dissolving Trans-scleral Microneedles for Intraocular Delivery of Cyclosporine A.

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases.

Gentamicin Eluting 3D-Printed Implants for Preventing Post-Surgical Infections in Bone Fractures.

A surgically implantable device is an inevitable treatment option for millions of people worldwide suffering from diseases arising from orthopedic injuries. A global paradigm shift is currently underway to tailor and personalize replacement or reconstructive joints. Additive manufacturing (AM) has provided dynamic outflow to the customized fabrication of orthopedic implants by enabling need-based design and surface modification possibilities. Surgical grade 316L Stainless Steel (316L SS) is promising with its cost, strength, composition, and corrosion resistance to fabricate 3D implants. This work investigates the possibilities of application of the laser powder bed fusion (L-PBF) technique to fabricate 3D-printed (3DP) implants, which are functionalized with a multilayered antimicrobial coating to treat potential complications arising due to postsurgical infections (PSIs). Postsurgical implant-associated infection is a primary reason for implantation failure and is complicated mainly by bacterial colonization and biofilm formation at the installation site. PLGA (poly-d,l-lactide-co-glycolide), a biodegradable polymer, was utilized to impart multiple layers of coating using the airbrush spray technique on 3DP implant surfaces loaded with gentamicin (GEN). Various PLGA-based polymers were tested to optimize the ideal lactic acid: glycolic acid ratio and molecular weight suited for our investigation. 3D-Printed PLGA-GEN substrates sustained the release of gentamicin from the surface for approximately 6 weeks. The 3DP surface modification with PLGA-GEN facilitated cell adhesion and proliferation compared to control surfaces. The cell viability studies showed that the implants were safe for application. The 3DP PLGA-GEN substrates showed good concentration-dependent antibacterial efficacy against the common PSI pathogen Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). The GEN-loaded substrates demonstrated antimicrobial longevity and showed significant biofilm growth inhibition compared to control. The substrates offered great versatility regarding the in vitro release rates, antimicrobial properties, and biocompatibility studies. These results radiate great potential in future human and veterinary clinical applications pertinent to complications arising from PSIs, focusing on personalized sustained antibiotic delivery.

Inclusion Complex of Clomiphene Citrate with Hydroxypropyl-ß-Cyclodextrin for Intravenous Injection: Formulation and Stability Studies.

Clomiphene citrate is the first-line treatment for women with abnormal or failed ovulation. Currently, it is available as oral tablets, and the parenteral formulation does not exist. In this study, we prepared clomiphene citrate-hydroxypropyl-ß-cyclodextrin inclusion complex for its use in intravenous injection. The inclusion complex was characterized in the liquid state (phase solubility) and solid state by differential scanning calorimetry, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy analyses. The sterile intravenous injection containing 0.5% clomiphene citrate was prepared and characterized for its physical properties, assay, pH, and osmolality. A stability-indicating high-performance liquid chromatography (HPLC) method for the injection was developed. The HPLC method was validated for the assay, linearity, precision and repeatability, benchtop stability, and forced degradation to elute clomiphene isomers from the degradation products. The injection was packed in sterile 10-ml glass vials with butyl rubber stoppers and stored at 40°C, room temperature, and 4°C. The samples at 0, 0.5, 1, 2, 3, and 6 months were analyzed for clarity, pH, osmolality, and drug assay. The HPLC method was linear (R2 = 0.9999), precise (0.86% relative standard deviation), and stability indicating. The stability data at the accelerated (40°C) storage condition for 6 months showed satisfactory results: the drug assay in the injection was between 90 and 105%, the injection remained clear, pH was between 4.0 and 4.4, and osmolality was between 270 and 350 mOsm. The stability data suggests that the product is stable and meets the given analytical specifications.

3D-Printed Capsaicin-Loaded Injectable Implants for Targeted Delivery in Obese Patients.

Diet-induced obesity and hyperlipidemia are a growing public health concern leading to various metabolic disorders. Capsaicin, a major bioactive compound obtained from natural chili peppers, has demonstrated its numerous beneficial roles in treating obesity and weight loss. Current treatment involves either administration of antiobesity drugs or surgical procedures such as Roux-en-Y-gastric bypass or sleeve gastrectomy, both of which are associated with serious side effects and poor patient acceptance. Capsaicin, a pungent molecule, has low oral bioavailability. Therefore, there is a need for the development of site-specific drug delivery system for capsaicin. The present study is aimed at preparing and characterizing 3D-printed capsaicin-loaded rod-shaped implants by thermoplastic extrusion-based 3D printing technology. The implants were printed with capsaicin-loaded into a biodegradable polymer, polycaprolactone, at different drug loadings and infill densities. The surface morphology revealed a smooth and uniform external surface without any capsaicin crystals. DSC thermograms showed no significant changes/exothermic events among the blends suggesting no drug polymer interactions. The in vitro release studies showed a biphasic release profile for capsaicin, and the release was sustained for more than three months (~ 85% released) irrespective of drug loading and infill densities. The HPLC method was stability-indicating and showed good resolution for its analogs, dihydrocapsaicin and nordihydrocapsaicin. The implants were stable for three months at accelerated conditions (40°C) without any significant decrease in the assay of capsaicin. Therefore, capsaicin-loaded implants can serve as a long-acting injectable formulation for targeting the adipose tissue region in obese patients.

Cardiolipin for Enhanced Cellular Uptake and Cytotoxicity of Thermosensitive Liposome-Encapsulated Daunorubicin toward Breast Cancer Cell Lines.

Daunorubicin (DNR) and cardiolipin (CL) were co-delivered using thermosensitive liposomes (TSLs). 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] or DSPE-mPEG (2000) and CL were used in the formulation of liposomes at a molar ratio of 57:40:30:3:20, respectively. CL forms raft-like microdomains that may relocate and change lipid organization of the outer and inner mitochondrial membranes. Such transbilayer lipid movement eventually leads to membrane permeabilization. TSLs were prepared by thin-film hydration (drug:lipid ratio 1:5) where DNR was encapsulated within the aqueous core of the liposomes and CL acted as a component of the lipid bilayer. The liposomes exhibited high drug encapsulation efficiency (>90%), small size (~115 nm), narrow size distribution (polydispersity index ~0.12), and a rapid release profile under the influence of mild hyperthermia. The liposomes also exhibited ~4-fold higher cytotoxicity against MDA-MB-231 cells compared to DNR or liposomes similar to DaunoXome® (p < 0.001). This study provides a basis for developing a co-delivery system of DNR and CL encapsulated in liposomes for treatment of breast cancer.

Hispolon Cyclodextrin Complexes and Their Inclusion in Liposomes for Enhanced Delivery in Melanoma Cell Lines.

Hispolon, a phenolic pigment isolated from the mushroom species Phellinus linteus, has been investigated for anti-inflammatory, antioxidant, and anticancer properties; however, low solubility and poor bioavailability have limited its potential clinical translation. In this study, the inclusion complex of hispolon with Sulfobutylether-ß-cyclodextrin (SBEßCD) was characterized, and the Hispolon-SBEßCD Complex (HSC) was included within the sterically stabilized liposomes (SL) to further investigate its anticancer activity against melanoma cell lines. The HSC-trapped-Liposome (HSC-SL) formulation was investigated for its sustained drug delivery and enhanced cytotoxicity. The inclusion complex in the solid=state was confirmed by a Job's plot analysis, molecular modeling, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Proton nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy (SEM). The HSC-SL showed no appreciable deviation in size (<150 nm) and polydispersity index (<0.2) and improved drug encapsulation efficiency (>90%) as compared to control hispolon liposomes. Individually incorporated hispolon and SBEßCD in the liposomes (H-CD-SL) was not significant in loading the drug in the liposomes, compared to HSC-SL, as a substantial amount of free drug was separated during dialysis. The HSC-SL formulation showed a sustained release compared to hispolon liposomes (H-SLs) and Hispolon-SBEßCD liposomes (H-CD-SLs). The anticancer activity on melanoma cell lines (B16BL6) of HSC and HSC-SL was higher than in H-CD-SL and hispolon solution. These findings suggest that HSC inclusion in the HSC-SL liposomes stands out as a potential formulation approach for enhancing drug loading, encapsulation, and chemotherapeutic efficiency of hispolon and similar water insoluble drug molecules.

Niosomal formulation of hydroxytyrosol, a polyphenolic antioxidant, for enhancing transdermal delivery across human cadaver skin.

Hydroxytyrosol (HT), a naturally occurring polyphenol from the olive plant, is a potent antioxidant, cardioprotective, neuroprotective, and anti-inflammatory agent. Upon oral administration, HT undergoes rapid elimination within minutes and thus limiting its therapeutic utility. Due to its hydrophilic nature, percutaneous absorption and transdermal delivery of HT are very low. The aim of this research was to enhance the skin permeation of hydroxytyrosol using a niosome gel formulation. The formulations prepared with Span 60 as surfactant showed uniform particle size and high encapsulation efficiency (>90%). The niosome formulations showed a pseudoplastic behavior for topical application within the lipid/surfactant composition of 45-50%. The formulations showed a controlled release of HT compared to the HT solution. The flux of HT across human skin was increased by 28 and 4.4 fold compared to aqueous and ethanolic HT solutions, respectively (p < 0.001). The presence of lecithin lowered the flux and increased the retention of the formulations compared to HT solutions (p < 0.001). The formulations containing lecithin showed two-fold higher skin retention of hydroxytyrosol (p < 0.05). In conclusion, this study demonstrates niosome gel as a promising alternative to oral delivery of HT, providing sustained delivery and greater efficacy.

Enhanced Topical Co-delivery of Acyclovir and Lidocaine Gel Formulation Across Dermatomed Human Skin.

Acyclovir a widely used drug in the treatment of herpes simplex virus (HSV) infections and lidocaine a local anesthetic were combined in a topical gel formulation. The topical gel with Transcutol P (TP) or N-methyl 2-pyrrolidone (NMP) was prepared and tested for in vitro skin permeation across the intact and microneedle-treated human cadaver skin. The topical gels containing 5% each of acyclovir and lidocaine showed optimal pH, spreadability, and 100% drug release. The transdermal flux and skin retention of the gels were significantly higher compared to Generic 5% acyclovir ointment (Zovirax) (p < 0.001), and 5% lidocaine gel (numb gel) (p < 0.05). As expected, topical gels showed a very high increase in the skin permeation across microporated skin versus intact skin. In viral infections, skin is inflamed, and barrier integrity may be disrupted. The results of the present study are significant because the co-delivery formulation showed a very high increase in the skin permeation across intact and microporated skin (versus respective commercial formulations). The results of this study demonstrate enhanced co-delivery of acyclovir and lidocaine in a topical formulation across skin (intact or barrier compromised) for the treatment of herpes virus infections.

Stability-indicating HPLC method for acyclovir and lidocaine in topical formulations.

A simple, rapid and accurate stability-indicating HPLC assay was developed for the determination of acyclovir and lidocaine in topical formulations. Chromatographic separation of acyclovir and lidocaine was achieved using a reversed-phase C18 column and a gradient mobile phase (20 mm ammonium acetate pH 3.5 in water and acetonitrile). The degradation products of acyclovir and lidocaine in the samples were analyzed by ultra performance liquid chromatography-time of flight mass spectrometry. The HPLC method successfully resolved the analytes from the impurities and degradation products in the topical formulation. Furthermore, the method detected the analytes from the human skin leachables following the extraction of the analytes in the skin homogenate samples. The method showed linearity over wide ranges of 5-500 and 10-200 µg/ml for acyclovir and lidocaine in the topical product, respectively, with a correlation coefficient (r2 ) >0.9995. The relative standard deviations for precision, repeatability, and robustness of the method validation assays were <2%. The skin extraction efficiency for acyclovir and lidocaine was 92.8 ± 0.7% and 91.3 ± 3.2%, respectively, with no interference from the skin leachables. Thus, simultaneous quantification of acyclovir and lidocaine in the topical formulations was achieved.

Co-Delivery of Hispolon and Doxorubicin Liposomes Improves Efficacy Against Melanoma Cells.

Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.

Microemulsion and Microporation Effects on the Genistein Permeation Across Dermatomed Human Skin.

This study reports the microemulsion (ME) effects on the permeation of genistein across normal (intact) and microporated human skin. The genistein formulation was optimized to know the stable ME region in the pseudo-ternary phase diagrams and to maximize the skin permeation and retention of genistein. The phase diagrams were constructed with different oil phases, surfactants, and their combinations. The influence of formulation factors on the permeation through intact and microporated human skin was determined. Based on its wide ME region, as well as permeation enhancement effects, oleic acid was used as an oil phase with various surfactants and co-surfactants to further maximize the ME region and skin permeation. The water content in the formulation played an important role in the ME stability, droplet size, and flux of genistein. For example, the ME with 20% water exhibited 4- and 9-fold higher flux as compared to the ME base (no water) and aqueous suspension, respectively. Likewise, this formulation had demonstrated 2- and 4-fold higher skin retention as compared to the ME base (no water) and aqueous suspension, respectively. The skin microporation did not significantly increase the skin permeation of genistein from ME formulations. The ME composition, water content, and to a lesser extent the ME particle size played a role in improving the skin permeation and retention of genistein.

Personalization of Intravaginal rings by droplet deposition modeling based 3D printing technology.

Intravaginal rings (IVRs) are long-acting drug device systems designed for controlled drug release in the vagina. Commercially available IVRs employ a one-size-fits-all development approach, where all patients receive the same drug in similar doses and frequencies, allowing no space for dosage individualization for specific patients' needs. To allow flexibility for dosage individualization, this study explores the impact of infill-density on critical characteristics of personalized IVRs, manufactured using droplet deposition modeling three-dimensional (3D) printing technology. The model drug was dispersed on the surface of thermoplastic polyurethane pellets using an oil coating method. IVR infill-density ranged from 60 to 100 %. The compatibility of the drug and matrix was assessed using thermal and spectroscopic analyses. The IVRs were evaluated for weight, porosity, surface morphology, mechanical properties, and in vitro drug release. The results demonstrated high dimensional accuracy and uniformity of 3D-printed IVRs, indicating the robustness of the printing process. Increasing infill-density resulted in greater weight, storage modulus, Young's modulus, Shore hardness, and compression strength, while reducing the porosity of IVRs. All IVRs showed a controlled drug release pattern when tested under accelerated conditions of temperature for 25 days. Notably, greater infill-densities were associated with a decrease in the percentage of drug released. Overall, the study demonstrated that infill-density was an important parameter for personalizing the critical characteristics of the 3D-printed IVRs to fit individual patient needs.

Three-Dimensional Printing of Drug-Eluting Implantable PLGA Scaffolds for Bone Regeneration.

Despite rapid progress in tissue engineering, the repair and regeneration of bone defects remains challenging, especially for non-homogenous and complicated defects. We have developed and characterized biodegradable drug-eluting scaffolds for bone regeneration utilizing direct powder extrusion-based three-dimensional (3D) printing techniques. The PLGA scaffolds were fabricated using poly (lactic-co-glycolic acid) (PLGA) with inherent viscosities of 0.2 dl/g and 0.4 dl/g and ketoprofen. The effect of parameters such as the infill, geometry, and wall thickness of the drug carrier on the release kinetics of ketoprofen was studied. The release studies revealed that infill density significantly impacts the release performance, where 10% infill showed faster and almost complete release of the drug, whereas 50% infill demonstrated a sustained release. The Korsmeyer-Peppas model showed the best fit for release data irrespective of the PLGA molecular weight and infill density. It was demonstrated that printing parameters such as infill density, scaffold wall thickness, and geometry played an important role in controlling the release and, therefore, in designing customized drug-eluting scaffolds for bone regeneration.

Long-Acting Drug Delivery Technologies for Meloxicam as a Pain Medicine.

Meloxicam, a selective COX-2 inhibitor, has demonstrated clinical effectiveness in managing inflammation and acute pain. Although available in oral and parenteral formulations such as capsule, tablet, suspension, and solution, frequent administration is necessary to maintain therapeutic efficacy, which can increase adverse effects and patient non-compliance. To address these issues, several sustained drug delivery strategies such as oral, transdermal, transmucosal, injectable, and implantable drug delivery systems have been developed for meloxicam. These sustained drug delivery strategies have the potential to improve the therapeutic efficacy and safety profile of meloxicam, thereby reducing the frequency of dosing and associated gastrointestinal side effects. The choice of drug delivery system will depend on the desired release profile, the target site of inflammation, and the mode of administration. Overall, meloxicam sustained delivery systems offer better patient compliance, and reduce the side effects, thereby improving the clinical applications of this drug. Herein, we discuss in detail different strategies for sustained delivery of meloxicam.

Clinical outcomes of chemotherapy in cancer patients with different ethnicities.

BACKGROUND: Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup. RECENT FINDINGS: Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing.  Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed. CONCLUSION: Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.

Liposomal DQ in Combination with Copper Inhibits ARID1A Mutant Ovarian Cancer Growth.

Therapeutic strategies for ARID1A-mutant ovarian cancers are limited. Higher basal reactive oxygen species (ROS) and lower basal glutathione (GSH) empower the aggressive proliferation ability and strong metastatic property of OCCCs, indicated by the increased marker of epithelial-mesenchymal transition (EMT) and serving the immunosuppressive microenvironment. However, the aberrant redox homeostasis also empowers the sensitivity of DQ-Lipo/Cu in a mutant cell line. DQ, a carbamodithioic acid derivative, generates dithiocarbamate (DDC) in response to ROS, and the chelation of Cu and DDC further generates ROS and provides a ROS cascade. Besides, quinone methide (QM) released by DQ targets the vulnerability of GSH; this effect, plus the increase of ROS, destroys the redox homeostasis and causes cancer cell death. Also importantly, the formed Cu(DDC)2 is a potent cytotoxic anti-cancer drug that successfully induces immunogenic cell death (ICD). The synergistic effect of EMT regulation and ICD will contribute to managing cancer metastasis and possible drug resistance. In summary, our DQ-Lipo/Cu shows promising inhibitory effects in cancer proliferation, EMT markers, and "heat" the immune response.

Advancing Cancer Therapy with Copper/Disulfiram Nanomedicines and Drug Delivery Systems.

Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer efficacy, and its supplementation with copper (CuII) significantly potentiates the efficacy of DSF. However, the results of clinical trials have not yielded promising results. The elucidation of the anticancer mechanisms of DSF/Cu (II) will be beneficial in repurposing DSF as a new treatment for certain types of cancer. DSF's anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins. DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis. This review also discusses current drug delivery strategies for DSF alone diethyldithocarbamate (DDC), Cu (II) and DSF/Cu (II), and the efficacious component Diethyldithiocarbamate-copper complex (CuET).

Topical Delivery of Diacetyl Boldine in a Microemulsion Formulation for Chemoprotection against Melanoma.

This study aimed to develop a microemulsion formulation for topical delivery of Diacetyl Boldine (DAB) and to evaluate its cytotoxicity against melanoma cell line (B16BL6) in vitro. Using a pseudo-ternary phase diagram, the optimal microemulsion formulation region was identified, and its particle size, viscosity, pH, and in vitro release characteristics were determined. Permeation studies were performed on excised human skin using Franz diffusion cell assembly. The cytotoxicity of the formulations on B16BL6 melanoma cell lines was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay. Two formulation compositions were selected based on the higher microemulsion area of the pseudo-ternary phase diagrams. The formulations showed a mean globule size of around 50 nm and a polydispersity index of <0.2. The ex vivo skin permeation study demonstrated that the microemulsion formulation exhibited significantly higher skin retention levels than the DAB solution in MCT oil (Control, DAB-MCT). Furthermore, the formulations showed substantially higher cytotoxicity toward B16BL6 cell lines than the control formulation (p < 0.001). The half-maximal inhibitory concentrations (IC50) of F1, F2, and DAB-MCT formulations against B16BL6 cells were calculated to be 1 µg/mL, 10 µg/mL, and 50 µg/mL, respectively. By comparison, the IC50 of F1 was 50-fold lower than that of the DAB-MCT formulation. The results of the present study suggest that microemulsion could be a promising formulation for the topical administration of DAB.

Sustained Release Biodegradable Microneedles of Difluprednate for Delivery to Posterior Eye.

Purpose: Difluprednate ophthalmic emulsion (Durezol®) is currently used for the treatment of anterior uveitis; however, recent studies have shown that difluprednate can treat posterior eye conditions. Topical formulations limit the amount of drug capable of permeating to the posterior segment due to permeation barriers, lacrimation, and lymphatic clearance. Methods: Resomer®-based microneedle patches were fabricated for difluprednate using poly(acrylic acid) (PAA) for the rapidly dissolvable backing. The patches were analyzed for microneedle uniformity and sharpness using scanning electron microscopy, and the penetration depth was analyzed by confocal microscopy. Failure force necessary to break the microneedles and force needed to penetrate the sclera were analyzed by the texture analyzer. Difluprednate release and trans-scleral permeation studies on microneedles were performed using Franz diffusion cells. Results: The microneedles were uniform, sharp, and penetrated to 500 µm depth on sclera. The microneedles have a failure force proportional to the molecular weight (MW) of the polymer used. There was no correlation between failure force and the penetration force of the microneedles. The PAA backing dissolved within 30-40 min, while release studies showed a matrix diffusion-controlled release over the 7-day study. The amount of drug permeation and retention in the sclera were decreased with an increase in the MW of the Resomer and failure force of each array. Conclusions: Resomer-based microneedles have a potential application for the sustained release of difluprednate for posterior segment conditions.

Difluprednate-Hydroxypropyl-ß-Cyclodextrin-Based Ophthalmic Solution for Improved Delivery in a Porcine Eye Model.

Purpose: Difluprednate (DFP) is an approved corticosteroid, available as an ophthalmic emulsion (Durezol®), used to treat pain and inflammation of the eye following ocular surgeries. This study utilized hydroxypropyl-ß-cyclodextrin (HPBCD)-based DFP ophthalmic solution for improved ocular delivery. Methods: The DFP-HPBCD complex formation was studied in the liquid and solid states. Phase solubility, molecular docking studies, differential scanning calorimetry, and Fourier transform infrared spectroscopy suggested inclusion complexation of DFP and HPBCD. Results: DFP-HPBCD-based eye drops (solution) provided 16 and 26 times higher transcorneal permeation when compared to the suspension (no HPBCD, control) and Durezol, respectively (P < 0.001). In addition, ocular drug distribution studies conducted in continuously perfused whole porcine eyes showed DFP permeated into all of the ocular tissues in significantly higher amounts than Durezol. Conclusions: The solution-based eye drops in this study is iso-osmotic, safe, and more permeable in porcine eyes compared to Durezol.