Recent Updates on Nanocarriers for Drug Delivery in Posterior Segment Diseases with Emphasis on Diabetic Retinopathy.

In recent years, various conventional formulations have been used for the treatment and/or management of ocular medical conditions. Diabetic retinopathy, a microvascular disease of the retina, remains the leading cause of visual disability in patients with diabetes. Currently, for treating diabetic retinopathy, only intraocular, intravitreal, periocular injections, and laser photocoagulation are widely used. Frequent administration of these drugs by injections may lead to serious complications, including retinal detachment and endophthalmitis. Although conventional ophthalmic formulations like eye drops, ointments, and suspensions are available globally, these formulations fail to achieve optimum drug therapeutic profile due to immediate nasolacrimal drainage, rapid tearing, and systemic tearing toxicity of the drugs. To achieve better therapeutic outcomes with prolonged release of the therapeutic agents, nano-drug delivery materials have been investigated. These nanocarriers include nanoparticles, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), dendrimers, nanofibers, in-situ gel, vesicular carriers, niosomes, and mucoadhesive systems, among others. The nanocarriers carry the potential benefits of site-specific delivery and controlled and sustained drug release profile. In the present article, various nanomaterials explored for treating diabetic retinopathy are reviewed.

Finasteride-loaded nano-lipidic carriers for follicular drug delivery: preformulation screening and Box-Behnken experimental design for optimization of variables.

Finasteride (FIN), a 5-α reductase enzyme inhibitor is mainly used orally for the treatment of androgenic alopecia and benign prostate hyperplasia. The present study was undertaken for systematic optimization and assessment of the designed nanostructured lipid carriers (NLC) to enhance follicular delivery of FIN by topical administration. The NLCs were prepared by microemulsion method, by employing a 33 Box-Behnken design and subsequently confirmed by ANOVA analysis. Compritol ATO-888 and Fenugreek oil were selected as the solid lipid and liquid lipid respectively for the fabrication of NLCs. The formulations were characterized for particle size, zeta potential, entrapment efficiency, storage stability and in vitro drug release profile. Morphological profile of the NLCs nanocarriers was studied by transmission electron microscopy (TEM). The Fourier Transform Infrared Spectroscopy (FT-IR) spectrum and differential scanning calorimetry (DSC) thermogram demonstrated that FIN entrapment within NLCs was devoid of chemical interaction with the components. The prepared NLCs had satisfactory particle dimensions, zeta potential and entrapment efficiency. The numerical optimization process indicated the optimal NLC composition with 3 mg of SPC, 6 mg lipid and 5 mg of drug. NLCs loaded with FIN had acceptable particle size at 379.8 nm, zeta potential of -37.1 mV and an entrapment efficiency of 84%. Transmission electron microscopy indicated the spherical morphology. In vitro release profile indicated a fast initial release and subsequently a prolonged release of FIN from the carrier for 24 h. The release kinetics data displayed a Higuchi diffusion release model with the best match R2 value (0.848). Short-term stability tests conducted over 4 weeks at 6° and 25 °C demonstrated that the formulation could retain their initial properties during the test period.

Effects of delayed versus immediate umbilical cord clamping in reducing death or major disability at 2 years corrected age among very preterm infants (APTS): a multicentre, randomised clinical trial.

BACKGROUND: Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study. METHODS: In this long-term follow-up analysis of the multicentre, randomised APTS trial in 25 centres in seven countries, infants (<30 weeks gestation) were randomly assigned before birth (1:1) to have clinicians aim to delay clamping for 60 s or more or clamp within 10 s of birth, both without cord milking. The primary outcome was death or major disability (cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay) at 2 years corrected age, analysed in the intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12610000633088). FINDINGS: Between Oct 21, 2009, and Jan 6, 2017, consent was obtained for follow-up for 1531 infants, of whom 767 were randomly assigned to delayed clamping and 764 to immediate clamping. 384 (25%) of 1531 infants were multiple births, 862 (56%) infants were male, and 505 (33%) were born before 27 weeks gestation. 564 (74%) of 767 infants assigned to delayed clamping and 726 (96%) of 764 infants assigned to immediate clamping received treatment that fully adhered to the protocol. Death or major disability was determined in 1419 (93%) infants and occurred in 204 (29%) of 709 infants who were assigned to delayed clamping versus 240 (34%) of 710 assigned to immediate clamping, (relative risk [RR]) 0·83, 95% CI 0·72-0·95; p=0·010). 60 (8%) of 725 infants in the delayed clamping group and 81 (11%) of 720 infants in the immediate clamping group died by 2 years of age (RR 0·70, 95% CI 0·52-0·95); among those who survived, major disability at 2 years occurred in 23% (144/627) versus 26% (159/603) of infants, respectively (RR 0·88, 0·74-1·04). INTERPRETATION: Clamping the umbilical cord at least 60 s after birth reduced the risk of death or major disability at 2 years by 17%, reflecting a 30% reduction in relative mortality with no difference in major disability. FUNDING: Australian National Health and Medical Research Council.

Nano-Lipidic Carriers as a Tool for Drug Targeting to the Pilosebaceous Units.

The pilosebaceous unit is the triad comprising of hair follicle, arrector pilli muscle, and sebaceous gland. Drug delivery to and through the hair follicles has garnered much attention of the researchers and the hair follicles represent an attractive target site via topical applications. They are bordered by capillaries and antigenpresenting cells, connected to the sebaceous glands and the bulge region of the hair follicle anchors the stem cells. The nano lipid carriers have the propensity to penetrate through the skin via transcellular route, intracellular route and follicular route. It has been established that nano lipid carriers have the potential for follicular drug delivery and provide some advantages over conventional pathways, including improved bioavailability, enhanced penetration depth, fast transport into the skin, tissue targeting and form a drug reservoir for prolonged release. This review describes the pilosebaceous unit (PSU) and related diseases and the recent lipid-based nanotechnology approaches for drug delivery to the follicular unit as well as related issues. Different types of nano lipid carriers, including ethosomes, liposomes, nanoparticles, solid lipid nanoparticles (SLNs), and nano lipid carriers (NLCs) have been reported for follicular drug delivery. Targeted drug delivery with nano-lipid carriers has the potential to augment the efficacy of drugs/bioactives to treat diseases of PSU. This review systematically introduces the activities of different formulations and the use of nano lipid carriers in treating PSU related disorders like alopecia, acne, and hirsutism.

Potential of chitosan-based carrier for periodontal drug delivery.

Periodontal diseases are chronic infectious diseases and are a major oral health burden. With the progress in the understanding of etiology, epidemiology and pathogenesis of periodontal diseases coupled with the understanding of the polymicrobial synergy in the dysbiotic oral microbial flora, several new therapeutic targets have been identified. The strategies to curb bacterial growth and production of factors that gradually destroy the tissue surrounding and supporting the teeth have been the cornerstone for inhibiting periodontitis. Systemic administration of antibiotics for the treatment of periodontitis have shown several drawbacks including: inadequate antibiotic concentration at the site of the periodontal pocket, a rapid decline of the plasma antibiotic concentration to sub-therapeutic levels, the development of microbial resistance due to sub-therapeutic drug levels and peak-plasma antibiotic concentrations which may be associated with various side effects. These obvious disadvantages have evoked an interest in the development of localized drug delivery systems that can provide an effective concentration of antibiotic at the periodontal site for the duration of the treatment with minimal side effects. A targeted sustained release device which could be inserted in the periodontal pocket and prolong the therapeutic levels at the site of action at a much lower dose is the need of the hour. Chitosan, a deacetylated derivative of chitin has attracted considerable attention owing to its special properties including antimicrobial efficacy, biodegradability, biocompatibility and non-toxicity. It also has the propensity to act as hydrating agent and display tissue healing and osteoinducting effect. The aim of this review is to shine a spotlight on the chitosan based devices developed for drug delivery application in the effective treatment of various periodontal disorders. The chitosan based carriers like fibers, films, sponge, microparticles, nanoparticles, gels that have been designed for sustained release of drug into the periodontal pocket are highlighted.

Application of nanocarrier-based drug delivery system in treatment of oral cancer.

Oral cancer includes cancer of lips, oral cavity and oropharynx. Oral cancer is the sixth most life-threatening disease affecting 65% of population. The delivery of cytotoxic chemotherapeutic anticancer drugs is a challenging task due to unfavorable properties. Both synthetic chemotherapeutic agents and herbal constituents are used in treatment of oral cancer. The purpose of present article is to overcome the limitations through concept of nanotechnology and conjugation approach. Also, it will provide better therapeutic effect and sustain long life of healthy and recovered cells. Moreover, development in this area will raise opportunities for the oncologist, researchers and pharmaceutical scientists. This review summarizes the clinical findings and patents on various oral anticancer drugs for effective pharmacotherapeutics.

PLGA nanoparticles for ocular delivery of loteprednol etabonate: a corneal penetration study.

The purpose of the present study was to develop loteprednol etabonate (LE) loaded poly(d,l-lactide co-glycolide) (PLGA) nanoparticles (NPs) and study their penetration profile into the excised goat cornea. In the present study, LE loaded PLGA NPs were prepared by solvent evaporation with high speed homogenization method and the penetration profile was studied using confocal laser scanning microscopy (CLSM). Rhodamine (Rd) was used as a fluorescent marker to prepare Rd-LE-PLGA-NPs. The NPs were characterized for particle size, X-ray diffraction (XRD), differential scanning calorimetry (DSC), transmission electron microscopy (TEM), drug entrapment, and permeation profile. Intense fluorescence observed across the depths of goat corneal tissue suggested an improved penetration profile of NPs. The entrapment efficiency and mean diameter of the optimized formulation (F5) were found to be 96.31 ± 1.68% and 167.6 ± 0.37 nm, respectively. These findings indicate that LE loaded PLGA NPs may serve as a potential drug carrier for ocular administration in eye disease.

Loteprednol Etabonate Nanoparticles: Optimization via Box-Behnken Design Response Surface Methodology and Physicochemical Characterization.

BACKGROUND: Abstract: The objective of the present work was to prepare and optimize the loteprednoletabonate (LE) loaded poly (D,L-lactide co-glycolide) (PLGA) polymer based nanoparticle carrier. The review on recent patents (US9006241, US20130224302A1, US2012/0028947A1) assisted in the selection of drug and polymer for designing nanoparticles for ocular delivery applications. METHODS: The nanoparticles were prepared by solvent evaporation followed by high speed homogenization. Biodegradable polymer PLGA (50:50) grade was utilized to develop various formulations with different drug:polymer ratio. A Box-Behnken design with 33 factorial design was selected for the present study and 17 runs were carried out in totality. The influence of various process variables (viz., polymer concentration, homogenization speed and sonication time) on the characteristics of nanoparticles including the in vitro drug release profile were studied. RESULTS: The nanoparticulate formulations were evaluated for mean spherical diameter, polydispersity index (PDI), zeta potential, surface morphology, drug entrapment and in-vitro drug release profile. The entrapment efficiency, drug loading and mean particle size were found to be 96.31±1.68 %, 35.46±0.35 % and 167.6±2.1 nm respectively. CONCLUSION: The investigated process and formulation variables were found to have significant effect on the particle size, drug loading (DL), entrapment efficiency (EE), and in vitro drug release profile. A biphasic in vitro drug release profile was apparent from the optimized nanoparticles (NPs) for 24 hours.

Medical management of glaucoma: focus on ophthalmologic drug delivery systems of timolol maleate.

Eye is a vital organ of our body and any complication not only poses the risk of serious medical condition but also economic burden on the individual. Timolol maleate is one of the preferable therapeutic agents for the management of glaucoma. Globally, eye drops are among the most common and popular conventional formulations, but they are also associated with some limitations in terms of therapeutic response, bioavailability, dosing frequency and poor patient compliance. Present paper gives an overview of the drug delivery systems developed for management of glaucoma, advances and novel approaches with special emphasis on timolol drug delivery.

Biofilm-mediated Antibiotic-resistant Oral Bacterial Infections: Mechanism and Combat Strategies.

Oral diseases like dental caries and periodontal disease are directly associated with the capability of bacteria to form biofilm. Periodontal diseases have been associated to anaerobic Gram-negative bacteria forming a subgingival plaque (Porphyromonas gingivalis, Actinobacillus, Prevotella and Fusobacterium). Biofilm is a complex bacterial community that is highly resistant to antibiotics and human immunity. Biofilm communities are the causative agents of biological developments such as dental caries, periodontitis, peri-implantitis and causing periodontal tissue breakdown. The review recapitulates the latest advancements in treatment of clinical biofilm infections and scientific investigations, while these novel anti-biofilm strategies are still in nascent phases of development, efforts dedicated to these technologies could ultimately lead to anti-biofilm therapies that are superior to the current antibiotic treatment. This paper provides a review of the literature focusing on the studies on biofilm in the oral cavity, formation of dental plaque biofilm, drug resistance of bacterial biofilm and the antibiofilm approaches as biofilm preventive agents in dentistry, and their mechanism of biofilm inhibition.

Topical Analgesic Nanolipid Vesicles Formulation of Capsaicinoids Extract of Bhut Jolokia (Capsicum chinense Jacq): Pharmacodynamic Evaluation in Rat Models and Acceptability studies in Human Volunteers.

Capsicum fruit is used for treating skeletomuscular disorders as a counterirritant analgesic around the globe. But its concentration-dependent irritation and concomitant withdrawal of therapy by the patients hampers its therapeutic usefulness. In the present study, a novel nanolipid approach based on elastic phospholipid vesicles was employed to encapsulate a semipurified extract of Bhut Jolokia for topical drug delivery application. The working hypothesis was that encapsulation of irritant extract into nanolipid vesicles may prevent the initial rejection of formulation and the elastic vesicles may facilitate deeper skin penetration over a shorter time period. Surface response methodology was adopted to study the effect of selected independent formulation variables on dependent variables like vesicle size and entrapment efficacy. The prepared formulations were characterized for various physicochemical parameters. The efficacy of the newly developed nonolipid vesicle formulation loaded with semipurified extract of Bhut Jolokia was tested on carrageenan and formaldehyde-induced inflammation as well as Freund's adjuvant-induced arthritis model. The novel formulations were tested on human volunteers in a Phase I clinical trial and were found to be acceptable. The study indicates that this strategy holds immense potential for topical delivery of the bioactive from Bhut Jolokia and can pave the way for its clinical applications.

Recent Advances in Ocular Drug Delivery, with Special Emphasis on Lipid Based Nanocarriers.

Eye is a vital sense organ of our body and any disorder can lead to serious medical implications that may put great financial burden on patient and their family. Effective drug delivery to the eye is a challenging proposition for the pharmaceutical scientist. Eye drops have been globally accepted as a formulation for anterior segment applications. On one hand it is widely used owing to its convenience but is also associated with some limitations in terms of desired pharmacological and pharmacokinetic profile, dosing frequency, systemic untoward effects, patient noncompliance, low drug bioavailability due to transient contact time, rapid washout by tearing and nasolacrimal drainage. The need to overcome these major issues related to ocular pharmacotherapy has been long recognized. Several novel nanocarriers including nanolipid based carrier systems have been widely explored and investigated for ophthalmic applications. These include solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes, in situ gels, niosomes, mucoadhesive systems and discomes. Since lipids have similar structure to human cell lipids, their biodegradable, non-toxic and biocompatible profile are particularly useful. Additionally, they also offer protection against drug degradation, impart controlled drug release characteristics and site specific delivery. This review explores the potential feasibility of lipid component in formulation of nanomedicine for ophthalmic delivery and reports the clinical findings in order to improve the ocular pharmacotherapy. Here, we also discussed for patents related to the topic.

Patent perspectives for corticosteroids based ophthalmic therapeutics.

Eye inflammation, if untreated at right time poses the risk of vision loss. Several categories of drugs are available in the global market, but corticosteroids are still used for the treatment of ocular inflammation including anterior/ posterior uveitis, age related macular degeneration (AMD) and post cataract surgery inflammation. Although corticosteroids have well-documented side effects as compared to non steroidal anti-inflammatory drugs (NSAIDs), but they are still regarded as better anti-inflammatory agents for treating ocular inflammations. The prime concern with conventional formulations such as (ophthalmic solutions, suspensions, ointments) is low drug bioavailability due to precorneal barrier of the eye, tear turnover and rapid drainage of drug via nasolacrimal drainage and drug induced systemic toxicity. To overcome these limitations, various novel formulations of corticosteroids have been explored. These include nanoparticles, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanomicelles, in-situ gels, iontophoresis, liposomes, nanoemulsions, microemulsions and ocular implants for the effective ophthalmic delivery of the corticosteroids. Topical nanocarriers have also been demonstrated to be promising vectors with potential application in the ophthalmic therapeutics. This review summarizes the clinical findings and patents on various corticosteroids as ocular pharmacotherapeutics.

Nanocarriers for ocular delivery for possible benefits in the treatment of anterior uveitis: focus on current paradigms and future directions.

INTRODUCTION: Many therapeutic strategies have been adopted in the treatment of anterior uveitis, and it includes corticosteroids and NSAIDs. But, the successful delivery of these drugs is restricted due to limitations of conventional formulation. This review emphasizes on the possible benefits and strategies for development of various novel nanocarriers. AREAS COVERED: The article explores the various polymers involved in the preparation of novel nanocarriers like polymeric nanoparticles, micelles, microemulsion, liposomes and cubosomes. Reported clinical experimental findings are screened and also discussed in this review. EXPERT OPINION: The principle behind the development of different nanocarriers is to overcome the limitations imposed by conventional formulations. Several efforts have been made by the researchers in achieving these objectives, but the major challenge with nanosystems remains the requirement of excipients that have unknown or objectionable toxicity profile and are not approved by regulatory authorities. This review is an attempt to provide comprehensive information for the scientists working in the concerned research area.

Penetration of tamoxifen citrate loaded ethosomes and liposomes across human skin: a comparative study with confocal laser scanning microscopy.

In the present study, ethosomal and liposomal formulations containing tamoxifen citrate were prepared and evaluated for their penetration properties in human cadaver skin using Franz diffusion cell and confocal laser scanning microscope (CLSM). The results clearly revealed that ethosomal vesicles showed a better drug permeation profile than that of liposomal vesicles. In addition, low fluorescence intensity in CLSM was recorded with liposomes as compared to ethosomes, indicating lower cumulative amount of drug permeation from liposomal vesicles. Furthermore, CLSM showed uniform fluorescence intensity across the entire depth of skin in ethosomal treatment, indicating high penetrability of ethosomal vesicles through human cadaver skin. In contrast, low penetrability of conventional liposomal vesicles was recorded as penetration was limited to the 7(th) section (i.e. upper epidermis layer) of skin as evident from visualization of intact liposomal vesicles in CLSM.

Tamoxifen citrate loaded ethosomes for transdermal drug delivery system: preparation and characterization.

Long term tamoxifen citrate therapy is imperative to treat several dermatological and hormonal sensitive disorders. Successful oral and parenteral administration of tamoxifen citrate has been challenging since it undergoes enzymatic degradation and has poor aqueous solubility issues. In the present work, tamoxifen citrate loaded ethosomes were prepared and characterized for transdermal applications. The prepared formulations were characterized for morphological features, particle size distribution, calorimetric attributes, zeta potential and drug entrapment. Permeation profile of prepared ethosomes was compared with liposomes and hydroethonalic solution across cellophane membrane and human cadaver skin. Results of the permeation studies indicate that ethosomes were able to deliver >90% drug within 24 hours of application, while liposomes and hydroethanolic solution delivered only 39.04% and 36.55% respectively. Skin deposition and stability studies are also reported.

Spontaneous pneumopericardium in a healthy full-term neonate.

Pneumopericardium is rare in neonates and might be of serious clinical significance. Neonatal pneumopericardium is usually a complication of mechanical ventilation in premature infants with respiratory distress syndrome. Here, the authors report a full-term neonate who developed spontaneous pneumopericardium which resolved spontaneously.

Nanosuspension: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to amphotericin B.

Present limitations in the management of ophthalmic fungal infections include the inability to provide long-term extraocular drug delivery without compromising intraocular structures and/or systemic drug exposure. In the present study, the potential of Eudragit RS 100 nanoparticles (NPs) as a new vehicle for the improvement of the delivery of drugs to the ocular mucosa was investigated. Amphotericin B (AmB) was chosen as a model compound because of its potential usefulness for the treatment of fungal diseases. A solvent displacement technique was used to produce AmB-loaded Eudragit NPs. These NPs had a mean size range of 150-290 nm and a zeta potential of +19-28 mV. Even after 6 months of stability study, results were unchanged, indicating the good potential for ocular application. In vitro release studies revealed that a maximum amount of drug was released within 24 hours (60%). The results obtained from microbial assay showed that the antifungal activity of drug-loaded NPs was equal to or slightly lower than that of free-AmB solution. In vivo experiments showed that, following topical instillation of nanosuspension to a rabbit's eye there was no irritation. From these results we can conclude that Eudragit RS 100 nanosuspension may represent an efficacious vehicle to deliver the drug into the eye. FROM THE CLINICAL EDITOR: Amphotericin B encapsulated into Eudragit, a mildly cationic nanoparticle, was shown to have 6 month stability, release 60% of its drug payload in dissolution within 24 hours, and elicited no irritation when instilled into rabbit eyes. The concept is being considered for local ophthalmologic therapy of fungal disease.

Design of Eudragit RL 100 nanoparticles by nanoprecipitation method for ocular drug delivery.

The objective of the current study was to prepare positively charged amphotericin-B-loaded nanoparticles providing a controlled release formulation. The particles were prepared by solvent displacement or nanoprecipitation method. The non-biodegradable positively charged polymer Eudragit RL 100 was used to prepare the different formulations with varying ratios of drug and polymer. The formulations were evaluated in terms of particle size, zeta potential, and differential scanning calorimetry measurements. Drug entrapment and release properties were examined also. The antimicrobial activity against Fusarium solani was determined. In vivo eye irritation study was carried out by a modified Draize test. All the formulations remained within a size range of 130 to 300 nm in fresh preparation as well as after 2 months. The zeta potential was positive (+22 to +42 mV) for all the formulations and was suitable for ophthalmic application. A prolonged drug release was shown by all the formulations. The formulation possesses a good antifungal activity against Fusarium solani when tested by disk diffusion method, and no eye irritation on in vivo testing was found. FROM THE CLINICAL EDITOR: The objective of the current study was to prepare positively charged amphotericin-B-loaded nanoparticles providing a controlled release formulation. The described formulation displayed good antifungal activity against Fusarium solani when tested by disk diffusion method, and no eye irritation on in vivo testing was found.