Development of posaconazole nanocrystalline solid dispersion: preparation, characterization and in vivo evaluation.

OBJECTIVE: Posaconazole (PCZ) is an antifungal drug, which acts by inhibiting the lanosterol-14α-demethylase enzyme. It is a biopharmaceutical classification system class II drug with its bioavailability being limited by poor aqueous solubility. The aim of this study was to improve the oral bioavailability of PCZ by preparing nanocrystalline solid dispersion (NCS). METHODS: PCZ-NCS was prepared by a combination of precipitation and high-pressure homogenization followed by freeze-drying. Several different surfactants and polymers were screened to produce NCS with smaller particle size and higher stability. RESULTS: The optimized NCS formulation containing 0.2% Eudragit S100 and 0.2% SLS was found to provide the average particle size of 73.31 ± 4.7 nm with a polydispersity index of 0.23 ± 0.03. Scanning electron microscopy revealed the preparation of homogeneous and rounded particles. Differential scanning calorimetry and X-ray diffraction confirmed crystalline nature of NCS. Nanonization increased the saturation solubility of PCZ by about 18-fold in comparison with the neat drug. Intrinsic dissolution study showed 93% dissolution of PCZ within the first 10 min. In vivo pharmacokinetic study in Wistar rats showed that Cmax and AUCtotal of PCZ-NCS increased by 2.58- and 2.64-fold compared to the marketed formulation. CONCLUSION: PCZ-NCS formulation presents a viable approach for enhancing the oral bioavailability of PCZ.

Designing a nanothermometer using gel-to-liquid phase transition property of hybrid niosome.

The gel-to-liquid phase transition property of a hybrid niosome, which is made with a non-ionic surfactant, span 60 (S60), and triblock copolymer L64, is effectively utilized to design a nanothermometer for temperature sensing in the physiological range (20 °C to 50 °C). The fluorescence signal of a polarity-sensitive probe, Coumarin 153, loaded into the niosome, is used as an indicator for temperature sensing. Due to its excellent temperature sensitivity and resolution, the sensor is capable of sensing temperature inside FaDu cells.

Bimetallic Ag-Cu Alloy SERS Substrates as Label-Free Biomedical Sensors: Femtomolar Detection of Anticancer Drug Mitoxantrone with Multiplexing.

Surface-enhanced Raman spectroscopy (SERS) has been recognized as a promising label-free technology for clinical monitoring due to its high sensitivity and multiplexing ability, which should accelerate the screening of important drugs in the blood and plasma of cancer patients in a simpler, faster, and less-expensive manner. In this work, bimetallic Ag-Au and Ag-Cu alloy microflowers (MFs) with tunable surface compositions were fabricated on a glass cover slip by simple thermolysis of a metal alkyl ammonium halide precursor and used as SERS substrates for the sensitive detection of anticancer drug mitoxantrone (MTO). Two different laser excitation sources, 532 and 632.8 nm, were used to explore the possibility of surface-enhanced resonance Raman scattering. The Ag-Cu substrate showed superior detection capability over Ag-Au, whereby the sensor recorded a noteworthy "limit of detection" value of 1 fM for MTO. Theoretical electromagnetic field maps were simulated on appropriately chosen plasmonic systems to compare the electromagnetic field enhancements with the experimental SERS efficiencies of the substrates. Further, using a 10% Ag-Cu substrate, efficient multiplexing detection of MTO was demonstrated with another anticancer drug doxorubicin (DOX) in water and mouse blood plasma.

Buccal mucosal application of dissolvable microneedle patch containing photosensitizer provides effective localized delivery and phototherapy against oral carcinoma.

The effectiveness of phototherapy using photosensitizers is limited by the challenges in their delivery at the site of irradiation. Here, we demonstrate the localized application of a photosensitizer-loaded microneedle patch for effective photodynamic and photothermal therapy in oral carcinoma. Indocyanine green (ICG) was studied as a photosensitizer for its effect on oral carcinoma, FaDu cells. Different parameters including concentration, near-infrared (NIR) laser irradiation intensity and irradiation time were optimized while measuring temperature increase and reactive oxygen species (ROS) generation in FaDu cells. A dissolvable microneedle (DMN) patch made of sodium carboxymethyl cellulose and sodium alginate was fabricated by the micromolding technique. DMN showed sufficient mechanical strength for insertion in the excised porcine buccal mucosa. DMN dissolved within 30 s in phosphate buffer and 30 min in the excised buccal mucosa. Confocal microscopy studies revealed DMN penetration up to a depth of 300 µm within the buccal mucosa. ICG-DMN applied on the back of the rat was found to be localized at the application site before and after irradiation using an 808 nm NIR laser. ICG-DMN was applied on the FaDu xenografted tumor model in athymic nude mice. The localized temperature increase and ROS generation significantly (P < 0.05) decreased the tumor volume after ICG-DMN application compared with the control group. In conclusion, DMN can be developed for the localized administration of photosensitizers for phototherapy in oral carcinoma.

Hydrocaffeic acid-chitosan coating of gastric patch provides long-acting mucoadhesive delivery of model chemotherapeutic agent.

The development of a long-acting orally administered dosage form is a challenge. Here, we report development of a multi-layered mucoadhesive gastric patch that could deliver entrapped chemotherapeutic agent for eight days after oral administration. The multi-layered patch was designed to contain core layer, mucoadhesive layer and backing layer. The core layer contained the model chemotherapeutic agent, regorafenib. The mucoadhesive layer made of chitosan-hydrocaffeic acid conjugate showed greatest mucoadhesion strength of 18.1 ± 0.78 kPa in freshly excised rat gastric mucosa. The backing layer made of hydrophobic polycaprolactone-polydimethylsiloxane composite showed the contact angle of 120 ± 4.7° after placement of water drop. The entrapped regorafenib predominantly released from the mucoadhesive-side of the patch into simulated gastric fluid and showed a zero-order release profile. The patches were found to be stable for desired characteristics for up to 3 months in long term storage conditions. The pharmacokinetic studies in rat model revealed constant plasma concentration of regorafenib sustained for 8 days after oral administration of gastric patch. The gastric tissue where the patch adhered for 8 days did not show any significant histological changes compared with the normal gastric tissue. The oral administration of single dose of regorafenib-loaded gastric patch in FaDu cell xenografted tumor bearing athymic nude mice has shown significant (P < 0.05) reduction in the tumor volume over 7 days compared to the control group. Taken together, the multi-layered mucoadhesive gastric patch can be developed as a long-acting oral drug delivery system.

Selective inhibition of PKR by C16 accelerates diabetic wound healing by inhibiting NALP3 expression in mice.

OBJECTIVE AND DESIGN: To understand the expression of dsRNA-dependent protein kinase R (PKR) in impaired diabetic wounds, hyperglycemia was induced in C57/BL6 mice with streptozotocin. Murine macrophage cell line, Raw 264.7, stimulated with high glucose and LPS was used to mimic diabetic wound environment in in-vitro. MATERIALS: Macrophages stimulated with HG + LPS, in presence and absence of PKR inhibitor (C16) and wound tissue samples from topically treated mice with C16, were analyzed for the expression of PKR, NALP3, active caspase-1, mature IL-1ß and phosphorylation of PKR and eIF2α. Wounds tissues were also analyzed for inflammatory cell infiltration by immunohistochemistry, angiogenesis by CD31 staining, collagen expression by western blotting, expression of CD206+ macrophages by flow cytometry and wound strength by texture analyzer. RESULTS: PKR and NALP3 were found to be upregulated in macrophages stimulated with HG + LPS as well as in impaired diabetic wounds. PKR inhibition using C16 ameliorated expression of NALP3, caspase-1, IL-1ß and phosphorylation of PKR and eIF2α, in macrophages and also in diabetic wounds. Treatment with C16 promoted the wound healing in diabetic mice by increasing collagen synthesis, reducing infiltration of F4/80+ macrophages and MPO+ neutrophil cells, increased angiogenesis, and increased number of M2 macrophages. CONCLUSION: PKR inhibition using C16 accelerates the wound healing process in diabetic mice by decreasing NALP3-mediated IL-1ß maturation.

Colon-Targeted Layer-by-Layer Self-assembled Film: Pharmacokinetic Analysis of BCS Class I and Class III Model Drugs.

The aim of the study was to investigate the pharmacokinetic parameters of 5-fluorouracil (5FU) and moxifloxacin HCl (MF) after oral administration using layer-by-layer assembled film in enteric-coated capsule. The layer-by-layer (LbL) film was prepared by sequential layering of chitosan and sodium alginate polyelectrolytes containing either 5FU or MF. The films were in vitro evaluated for physical characteristics, drug loading and release behaviour. In vivo pharmacokinetic evaluation was performed in the rat model for three different drug concentrations after oral administration and compared with intravenous administration. The results showed that the thickness of 10-bilayer film was 147 ± 11.66 µm and 212.3 ± 7.19 µm after 5FU and MF loading, respectively. The LbL film with backing layer provided directional release of 5FU and MF, where 63.81 ± 4.52% and 101.38 ± 5.08%, respectively, was released in 24 h. 5FU showed non-linear pharmacokinetics compared with linear pharmacokinetics shown by MF after oral administration. There is a dose-dependent increase in Cmax after oral administration of 5FU and MF LbL film. The Tmax was found to be 720 min and 840 min for 5FU and MF after oral administration. The mean residence time and AUC0-24 at 45 mg/kg were 871.4 ± 6.45 min and 198.6 ± 5.03 × 103 min per ng/mL and 1267 ± 142.4 min and 1590 ± 55.60 103 min per ng/mL for 5FU and MF, respectively. Taken together, colon-targeted LbL film can be developed for oral administration of drugs for local and systemic applications.

Transfersome Hydrogel Containing 5-Fluorouracil and Etodolac Combination for Synergistic Oral Cancer Treatment.

Oral cancer is one of the most common malignancies with an increased rate of incidence. 5-Fluorouracil (5FU) is an effective chemotherapeutic indicated for oral cancer treatment. Etodolac (Et), a cyclooxygenase-2 inhibitor, can be used as an adjuvant agent to sensitize cancer cells to chemotherapy. The aim of this work was to prepare and characterize 5FU and Et dual drug-loaded transfersomes to treat oral cancer. Transfersomes were prepared by thin-film hydration method and characterized for the average particle size and zeta-potential using dynamic light scattering and scanning electron microscopy techniques. The prepared transfersomes were further characterized for their drug loading, entrapment efficiencies using amicon centrifuge tubes and drug release behavior using cellulose membrane. The synergistic activity of dual drug-loaded transfersomes was studied in FaDu oral cancer cells. Results showed that the average particle size, polydispersity index, and zeta potential were 91±6.4 nm, 0.28±0.03, and (-)46.9±9.5 mV, respectively, for 5FU- and Et (1:1)-loaded transfersomes. The highest encapsulation efficiency achieved was 36.9±3.8% and 79.8±6.4% for 5FU and Et (1:1), respectively. Growth inhibition studies in FaDu cells using different concentrations of 5FU and Et showed a combination index of 0.36, indicating a synergistic effect. The FaDu cell uptake of drug-loaded transfersomes was significantly (p<0.05) greater than that of free drugs. The transfersome hydrogel made of HPMC (2% w/w) showed similar flux, lag time, and permeation coefficient as that of drug-loaded transfersomes across excised porcine buccal tissue. In conclusion, 5FU and Et transfersome hydrogel can be developed for localized delivery to treat oral cancer.

Functionalized LbL Film for Localized Delivery of STAT3 siRNA and Oxaliplatin Combination to Treat Colon Cancer.

The aim of the study was to develop and evaluate the efficacy of a functionalized layer-by-layer (LbL) assembled film entrapped with oxaliplatin (OX) and signal transducer and activator of transcription 3 (STAT3) siRNA in the localized treatment of colon cancer. The LbL film was prepared by the sequential layering of chitosan (CS) and alginate to attain desired physical and mechanical properties. The film was functionalized by coating folic acid-conjugated CS on one side. On the other side, polycaprolactone was coated as a backing layer to provide directional drug release. OX was entrapped within the layers of the film, while STAT3 siRNA was complexed with CS to form nanoparticles before entrapment in the LbL film. The CS-siRNA nanoparticles were taken up by the colon carcinoma, Caco-2 cells within 3 h and provided concentration-dependent reduction in STAT3 protein expression. The functionalized LbL film (F-LbL film) selectively adhered to the colon cancer tissue in the mice model, whereas the nonfunctionalized film adhered to the normal colon tissue. The combination of OX and STAT3 siRNA provided significantly greater tumor regression, survival rate, and STAT3 protein suppression after localized delivery through oral administration compared with intravenous administration. Taken together, the F-LbL film can selectively bind to colon tumors for localized delivery of drugs to treat colon cancer.

Microneedle scleral patch for minimally invasive delivery of triamcinolone to the posterior segment of eye.

The delivery of therapeutics to the posterior segment of the eye is achieved by invasive procedures, including intravitreal injections and implants. The topically applied formulations would not permeate through different tissue barriers of the eye to reach the posterior segment. Here, we demonstrate the effectiveness of microneedle scleral patch in delivering the model molecule, triamcinolone acetonide, to the posterior segment of the eye. Microneedle scleral patch (MSP) and microneedle corneal patch (MCP) were fabricated through the micromolding technique using rapidly dissolvable polyvinylpyrrolidone. The patches containing 25 microneedles were characterized for physical and mechanical properties, drug loading and release behavior in vitro and ex vivo porcine eye globe model. The distribution of TA administered using MSP and MCP in different ocular tissues was evaluated in the rabbit eye model. The results showed that microneedles with 545 ± 8 µm length and 279 ± 26 µm width at the base in MSP penetrate the scleral membrane with the application of 0.35 ± 0.06 N force. The needles dissolved within 60 s after insertion in the corneal and scleral tissue. The 5 min application of MSP showed a significantly (p < 0.05) greater TA disposition in the vitreous humor and choroid-retinal complex in excised porcine eye globe compared with MCP and TA nanosuspension eye drops. In rabbit model studies, the TA concentration was greatest in the choroid-retinal complex and sclera after administration through intravitreal injection and MSP, respectively. The TA disposition in the sclera was significantly (p < 0.05) greater after MSP application compared with intravitreal injection and MCP application for up to 24 h. MSP application provided a greater safety score compared with intravitreal injection. In conclusion, MSP can be developed as a minimally invasive drug delivery system to target the posterior segment of the eye.

Red-emitting carbon nanoparticles with unprecedented singlet oxygen generation efficiency for cancer theranostics.

Fluorescent Red-emitting carbon nanoparticles (RCNPs) are produced by an economical and green hydrothermal method using Eucalyptus leaves as a precursor. This is the first report of its kind demonstrating RCNPs in combined PDT-Chemo combination therapy, as RCNPs bind with mitoxantrone (MTO) electrostatically. The synthesized RCNPs before and after conjugation of MTO are characterised using DLS, SEM, TEM, UV-Vis, Fluorescence, FTIR, and 1H NMR Spectroscopy. FTIR and 1H NMR confirm the interaction between -NH proton of MTO with carboxylic acid oxygen of RCNPs. RCNPs are demonstrated as brightly fluorescent, type II photosensitizer (PS) with an extraordinary 1O2 quantum yield of 0.96, when triggered with a red laser at 660 nm. Moreover, the biocompatibility of RCNPs and RCNPs-MTO are examined and confirmed by performing a cytotoxicity assay on MCF-7 cell lines. Subsequently, to explore the internalization process of the RCNPs as a function of concentration, confocal imaging study is also carried out. The cell viability and the apoptosis assay indicates that RCNPs-MTO can achieve the PDT-Chemo synergistic cancer therapy. To the best of our knowledge, this is the first time that Eucalyptus leaves, a natural source of great abundance, is used as raw material and applied for combined PDT-chemotherapy.

Functionalized polymeric patch for localized oxaliplatin delivery to treat gastric cancer.

Localized delivery of chemotherapeutic agents allows extended drug exposure at the target site, thereby reducing systemic toxicity. We report the development of functionalized polymeric patch with unidirectional drug release to treat gastric cancer. The oxaliplatin-loaded patch was prepared by incorporating sodium carboxymethyl cellulose, hydroxypropyl cellulose and polyvinylpyrrolidone. The patch was functionalized by coating with transferrin-poly(lactic-co-glycolic acid) conjugate on one side of the patch for cancer targeting. The other side of the patch was coated with ethylcellulose (EC) to restrict the release of oxaliplatin. The physical and mechanical properties of oxaliplatin-loaded patches were characterized. Mucoadhesion studies using excised rat stomach tissue have shown that the functionalized side of the patch has significantly (p < 0.05) greater mucoadhesion strength compared with EC coated side of the patch. The in vitro and ex vivo (stomach sac and open-membrane model) studies revealed greater permeation of oxaliplatin across the stomach tissue when adhered to the functionalized and non-functionalized side of the patch compared with EC coated side. It was found that the growth inhibition with oxaliplatin solution was not significantly greater compared with corresponding concentrations of oxaliplatin-loaded patch in AGS and Caco-2 cell models. The in vivo studies were performed in mice, where indocyanine green-loaded patch encapsulated in a gelatin capsule was orally administered. The near-infrared (NIR) optical imaging revealed adherence of the patch on the mucosal side of the stomach tissue for up to 6 h. In conclusion, the functionalized polymeric patch loaded with oxaliplatin can be a potential localized delivery system to target gastric cancer.

Transdermal delivery of vancomycin hydrochloride: Influence of chemical and physical permeation enhancers.

Topical and transdermal delivery of vancomycin hydrochloride (VH), a broad-spectrum peptide antibiotic, is a challenge because of its high molecular weight (1485.7 Da) and hydrophilicity (log P -3.1). The objective of this study was to investigate the feasibility of delivering VH into and across the skin using permeation enhancement techniques. Skin permeation studies were performed using Franz diffusion cell apparatus in the excised porcine skin model. The influence of co-treatment and pre-treatment of chemical permeation enhancers (oleic acid and palmitic acid) on permeation of VH across intact and tape-stripped skin was evaluated. In addition, continuous anodal iontophoresis was applied to enhance the skin permeation of VH. The mechanism of skin permeation enhancement by palmitic acid was investigated using FTIR spectroscopy, impedance spectroscopy, and thermal analysis techniques. Pharmacokinetic analysis was performed after the topical application of VH formulations in Sprague Dawley rats. Results from permeation studies showed that VH did not passively permeate across the intact skin after 48 h, whereas the cumulative amount of VH permeated across the tape-stripped skin was found to be 854 ± 67 µg/cm2. A combination of tape-stripping and chemical enhancers resulted in enhancing the cumulative amount of VH permeated across the skin by 2- and 10-fold with oleic acid and palmitic acid application, respectively. Similarly, 2 and 12 h pre-treatment of tape-stripped skin with palmitic acid enhanced the flux of VH across the skin by 1.7- and 5-fold, respectively. It was found that tape-stripping and the palmitic acid application would provide greater VH permeation compared with 0.31 mA/cm2 iontophoresis application. Thermal analysis and impedance spectroscopic analysis showed that palmitic acid interacts with epidermal lipids to enhance VH permeation. Pharmacokinetic analysis after topical application showed that the Cmax and mean residence time increased by 3-fold with the application of VH and palmitic acid on tape-stripped skin compared with free VH on intact skin. Taken together, VH can be delivered through the topical route using a combination of chemical enhancer and tape-stripping to treat local and systemic bacterial infections.

Advanced materials for drug delivery across mucosal barriers.

Mucus is a viscoelastic gel that traps pathogens and other foreign particles to limit their penetration into the underlying epithelium. Dosage forms containing particle-based drug delivery systems are trapped in mucosal layers and will be removed by mucus turnover. Mucoadhesion avoids premature wash-off and prolongs the residence time of drugs on mucus. Moreover, mucus penetration is essential for molecules to access the underlying epithelial tissues. Various strategies have been investigated to achieve mucoadhesion and mucus penetration of drug carriers. Innovations in materials used for the construction of drug-carrier systems allowed the development of different mucoadhesion and mucus penetration delivery systems. Over the last decade, advances in the field of materials chemistry, with a focus on biocompatibility, have led to the expansion of the pool of materials available for drug delivery applications. The choice of materials in mucosal delivery is generally dependent on the intended therapeutic target and nature of the mucosa at the site of absorption. This review presents an up-to-date account of materials including synthesis, physical and chemical modifications of mucoadhesive materials, nanocarriers, viral mimics used for the construction of mucosal drug delivery systems.

Corneal delivery of moxifloxacin and dexamethasone combination using drug-eluting mucoadhesive contact lens to treat ocular infections.

The important causes of loss of vision are ocular infections, including keratitis and conjunctivitis. Attaining an adequate concentration of topically applied antibiotics to prevent or treat infections within the cornea is challenging. The study aimed to design and develop a drug-eluting polymeric contact lens for the effective delivery of moxifloxacin (MF) and dexamethasone (DM). The polymeric contact lens was prepared using chitosan, glycerol, and polyethylene glycol. MF and DM were loaded into the contact lens, both separately and in combination. The MF and DM loaded contact lenses were characterized for thickness, swelling index, surface topography, and mucoadhesion strength. Furthermore, studies were performed to understand the in vitro drug release behavior, ex vivo corneal permeation, and in vitro and in vivo antimicrobial activity. The drug-loaded contact lens was compared with the standard drug solutions. The physical characteristics of the polymeric contact lens were similar to the commercially available contact lens. Compared to the topically applied standard drug solutions, the drug-loaded contact lens showed significantly (p < 0.05) greater corneal drug distribution after 24 h incubation. In vitro and in vivo antimicrobial activity of the MF loaded contact lens was superior to the standard drug solution. In vivo drug distribution studies showed greater tissue concentration of MF in cornea, sclera, and aqueous humor with contact lens application compared with drug solutions. Overall, the polymeric contact lens was efficient in delivering MF and DM at required therapeutic concentrations. The findings from the present study show that drug-eluting contact lenses could be used in post-operative conditions to prevent ocular infections.

HDAC6 inhibitor accelerates wound healing by inhibiting tubulin mediated IL-1ß secretion in diabetic mice.

Delayed wound healing in diabetes is characterized by sustained activation of inflammasome and increased expression of IL-1ß in macrophages. Identification and validation of novel pathways to regulate IL-1ß expression will provide therapeutic targets for diabetic wounds. Here we report sustained over-expression of histone deacetylase 6 (HDAC6) in wounds of diabetic mice and its role in delayed wound healing. Topical application of HDAC6 inhibitor; Tubastatin A (TSA) gel promoted the wound healing in diabetic mice. TSA hydrogel reduced the infiltration of neutrophils, T-cells and macrophages in the early phase of wound healing. TSA treatment promoted the wound healing by inducing collagen deposition, angiogenesis (CD31) and fibrotic factors (TGF-ß1) in the late phase of healing. Protein analysis of the diabetic wounds treated with TSA showed increased acetylated α-tubulin and decreased levels of mature IL-1ß with no significant effect on the expression of pro-IL-1ß, pro-caspase-1 and active caspase-1. In in vitro assays, macrophages exhibited upregulation of HDAC6, IL-1ß and downregulation of IL-10 upon stimulation with high glucose and LPS. TSA inhibited the IL-1ß secretion and promoted IL-10 in stimulated macrophages with high glucose and LPS. Further investigations showed that TSA inhibits IL-1ß release by inhibiting tubulin dependent lysosomal exocytosis without affecting its transcription and maturation. Nocodazole (known acetylation inhibitor) pre-treatment inhibited TSA effect on IL-1ß secretion in high glucose stimulated macrophages. Overall, our findings indicate that sustained HDAC6 expression in diabetic wounds contributes to impaired healing responses and HDAC6 may represent a new therapeutic target for diabetic wounds.

Functionalized layer-by-layer assembled film with directional 5-fluorouracil release to target colon cancer.

The objective of this work was to prepare and characterize pH-sensitive capsule containing functionalized layer-by-layer (LbL) assembled polymeric film with directional drug release and evaluate its effectiveness against colon cancer. 5-Fluorouracil (5FU) loaded LbL film was prepared by sequential adsorption of chitosan and alginate polyelectrolytes. This LbL film was coated with polycaprolactone (PCL, 95% w/w) as a backing layer to restrict 5FU release on one-side. The other side constituted the folic acid conjugated chitosan layer for cancer targeting. This film was encapsulated into a gelatin capsule coated with pH-sensitive Eudragit S100. 5FU loaded LbL film was characterized for physical and mechanical properties. Mucoadhesion studies performed using excised rabbit colon showed that chitosan-side of LbL film adhered with significantly (p < 0.05) greater strength compared with PCL-side. Non-everted rat colon-sac model and open colon membrane model studies showed greater permeation of 5FU across the colon wall when adhered to chitosan-side of LbL film compared with PCL-side of the film. Cell monolayer and 3D-spheroid model studies using Caco-2 and COLO 320DM colorectal cancer cells showed significant (p < 0.05) growth inhibition by 5FU loaded LbL film compared with free 5FU solution. In conclusion, pH-sensitive capsule containing 5FU loaded LbL film can be developed to target colorectal cancer for regional drug delivery.

Microneedle ocular patch: fabrication, characterization, and ex-vivo evaluation using pilocarpine as model drug.

Context: Enhacing the ocular bioavailability of drugs after their topical application is a challenge.Objective: The objective of the study was to design, fabricate, and investigate the effectiveness of microneedle ocular patch (MOP) in delivering the model drug, pilocarpine HCl across the corneal membrane.Methods: MOP mimicked commercially available contact lens design elements having a diameter of 14.20 mm and a sagittal height of 3.85 mm with a convex curvature. The base of this patch contained an array of 25 pyramid-shaped microneedles measuring 521 ± 10 µm in length. Pilocarpine loaded MOP was prepared by micromolding technique using dissolvable polyvinyl alcohol and polyvinyl pyrrolidone matrix. MOP was characterized for physical and mechanical properties using a stereomicroscope, scanning electron microscope, and texture analyzer.Results: Histological examination after MOP application on excised human cornea showed penetration of microneedles with a required insertional force of 1.04 ± 0.17 N. Flux of pilocarpine across excised cornea was significantly (p < 0.05) greater after application of MOP (704 ± 149 µg/cm2/h) compared with solution formulation (188 ± 24 µg/cm2/h). Ex-vivo pilocarpine permeation study in porcine eye globe revealed significantly (p < 0.05) greater availability in aqueous humor within 30 min of application of MOP (249 ± 85 µg/ml) compared with solution formulation (46 ± 9 µg/ml).Conclusion: MOP can be developed as a potential ophthalmic drug delivery system.

Novel drug delivery methods for the treatment of keratitis: moving away from surgical intervention.

Introduction: Corneal ulceration is one of the leading causes of blindness especially in low- and mid-income countries (LMICs). Surgical treatment of microbial keratitis is associated with multiple challenges that include non-availability of donor corneal tissues, lack of trained corneal surgeons, and poor compliance to follow up care. As a result, the surgery fails in 70-90% cases. Therefore, improving outcome of medical treatment and thereby avoiding the need for the surgery is an unmet need in the care of corneal ulcer cases.Areas covered: In this review article, the authors have tried to compile information on the novel drug-delivery systems that have potential to enhance success of medical management. We have discussed the following systems: cyclodextrins, gel formulations, colloidal system, nanoformulations, drug-eluting contact lens, microneedle patch, and ocular inserts.Expert opinion: The goals of corneal ulcer treatment are as follows: rapid eradication of causative microorganisms, control of damage from induced inflammation and microbial toxins, and facilitation of repair. The ocular surface anatomy poses several challenges for drug delivery using standard topical therapy. The novel drug-delivery systems mentioned above aim to enhanced tear solubility; superior stability; improved bio-availability; reduced toxicity; besides facilitating targeted drug delivery and convenience of administration.