Ophthalmic Routes Research Articles

Are Alpha-2 Adrenergic Agonists Being Used in Infants?

Purpose: To identify and quantify adverse events (AEs) associated with alpha-2 adrenergic agonists prescribed for the treatment of glaucoma in infants. Methods: We queried the Federal Adverse Event Reporting System (FAERS) from 2004-2023Q1 for AE reports related to brimonidine use in patients aged 12 months or younger. We then conducted a disproportionality analysis using data mining algorithms, including the reporting odds ratio, proportional reporting ratio, empirical bayes geometric mean, and information component to identify significant symptoms. Results: We identified 35 unique AE reports associated with brimonidine. Of these, 27 cases involved hospitalization, 13 cases involved life-threatening complications, 18 cases reported other complications, and 1 case involved a congenital anomaly. The most commonly reported AE was hypotonia, occurring in 20 cases. This was followed by other systemic symptoms, including hypothermia, depressed level of consciousness, lethargy, general toxicity, and pallor, among others. All symptoms were found to be significant in the disproportionality analysis. Notably, most cases were not known to involve an ophthalmic route of exposure. Conclusions: The use of alpha-2 adrenergic agonists in infants aged 1 year or younger has been associated with various systemic AEs, including hypotension, respiratory depression, and central nervous system depression. Ophthalmologists should be aware of these potential risks. Further, more rigorous warnings should be in place to prevent unintentional exposure of infants to brimonidine.

Ophthalmic Atropine: A Typical Anticholinergic Toxidrome From an Atypical Old Culprit.

Included on the World Health Organization Model Lists of Essential Medicines, atropine remains a cornerstone medication that is used for a myriad of clinical indications. Systemically, atropine carries indications for the treatment of asymptomatic and symptomatic bradycardia, reduction of salivation and bronchial secretions prior to surgery, and as an antidote for a variety of poisoning agents (i.e., carbamate or organophosphate insecticides, nerve agents, muscarine-containing mushrooms). Topically, atropine is administered via the ophthalmic route for the treatment of cycloplegia, mydriasis, and amblyopia or may be administered sublingually to treat chronic sialorrhea. As an anticholinergic, supratherapeutic concentrations of atropine result in a toxidrome typical of other anticholinergic medication overdoses. However, it is easy to overlook atropine as the causative agent when being administered topically, potentially resulting in an unnecessarily extensive and complicated workup. This case report describes the systemic absorption of atropine administered through the ophthalmic route at normal doses, resulting in stroke-like symptoms in an adolescent male. Upon identifying that the patient was being treated with atropine ophthalmic drops prior to hospital arrival, a dose of intravenous physostigmine was administered, resulting in complete reversal of all toxidrome symptoms.

Pharmacokinetics and Safety of a Bilastine Once-Daily, Preservative-Free, Ophthalmic Formulation.

IntroductionBilastine is a second-generation H1 antihistamine indicated for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. On the basis of the demonstrated efficacy and safety of the oral formulation, a new ophthalmic formulation of bilastine was recently developed. Previous preclinical studies had indicated that bilastine is mainly absorbed by the conjunctiva and shows low plasma concentration. The objective of this study was to evaluate the pharmacokinetics and safety of ophthalmic bilastine (6 mg/mL) after single and multiple dose administration at steady state in healthy adults.MethodsThis was an open-label, single-centre, phase I, bioavailability clinical trial. One drop of the bilastine ophthalmic formulation was administered once daily in each eye of the subjects for 5 days. Bilastine plasma concentrations were measured by HPLC–MS/MS. Adverse drug reactions were recorded for each subject during drug administration and follow-up visits.ResultsTwelve healthy subjects (age 18–55 years) were included in the study. After multiple dose administration, bilastine reached a mean (± SD) maximum blood concentrations of 2682.26 ± 1615.88 pg/mL at a median time of 2.50 h (range 1.25–4.00 h). The half-life of bilastine in plasma was 7.88 ± 6.72 h. Steady state AUC was 19,512.51 ± 9248.76 h·pg/mL. Adverse events were mild and transient, consisting mainly of dysgeusia.ConclusionsBilastine once-daily ophthalmic formulation 6 mg/mL is absorbed into the bloodstream in low amounts by the ophthalmic route. The bilastine ophthalmic formulation showed a good safety profile after multiple dose administration.

A BASIC REVIEW ON MICRO EMULSION AS A DRUG DELIVERY SYSTEM.

Lipid dosage forms are attractive delivery systems for hydrophobic drug molecules. Emulsion is one of the popular system since many decades. Pharmaceutical applications of emulsions widened especially after micro emulsion emergence. Now a day Microemulsion is an emerging trade and having worldwide importance in a variety of technological applications. These applications include enhanced oil recovery, combustion, cosmetics, pharmaceuticals, agriculture, metal cutting, lubrication, food, enzymatic catalysis, organic and bio-organic reactions, chemical synthesis of nanoparticles etc. This review article deals with feature and application of microemulsion. a brief introduction and definition, structure, type, formation characteristics, stability, phase behavior and the effect of additives, pressure, temperature on the phase behavior of microemulsion . In addition to oral and intravenous delivery, they are amenable for sustained and targeted delivery through ophthalmic, dental, pulmonary, vaginal and topical routes. Microemulsions are experiencing a very active development as reflected by the numerous publications and patents being granted on these systems. They have been used to improve the oral bioavailability of various poorly soluble drugs including cyclosporine.
 Keywords: Microemulsion, Self micro emulsifying system, poor soluble, thermodynamically stable, Sustained & Controlled release, Drug delivery.

Applications, Model Study and Commercial Utilization (Patents) of Ophthalmic Route as Drug Delivery Site

Ophthalmic drug delivery has been a noteworthy challenge for the researchers because of its one of a kind anatomy and physiology which consists of different sorts of boundaries, such as layers of cornea, sclera, and retina, etc. these obstructions can cause challenges for drug delivery and also in a dosage form, significantly into the posterior part of the eye. To defeat these sorts of issues different types of dosage forms have been developed such as nanoparticles, nano micelles, liposome, and micro-emulsions. Ongoing endeavors in research for ophthalmic drug delivery principally have concentrated on the frameworks which demonstrated that drugs are administered as in the form of eye drops. Because of the intense efforts of researchers, huge progressions in the following areas have been made, areas like in situ forming gels, oil in water emulsions, colloidal drug delivery systems, etc. The present article represents the overview of various factors which affects absorption and also clarifies about the use of media like bio-relevant media for eyes. This review will also explains about the transport of peptides and proteins through eyes, factors governing precipitation of drugs into eyes, vaccination through eyes as well as mechanistic study for drug absorption. Additionally, this article also summarizes different patents which are based on ophthalmic delivery of active agents. Delivery of drugs by ophthalmic route has been proved advantageous for future perspectives.

Applications, Model Study and Commercial Utilization (Patents) of Ophthalmic Route as Drug Delivery Site

Applications, Model Study and Commercial Utilization (Patents) of Ophthalmic Route as Drug Delivery Site

Perspectives on Physicochemical and In Vitro Profiling of Ophthalmic Ointments.

Ophthalmic ointments are unique in that they combine features of topical drug delivery, the ophthalmic route and ointment (semisolid) formulations. Accordingly, these complex formulations are challenging to develop and evaluate and therefore it is critically important to understand their physicochemical properties as well as their in vitro drug release characteristics. Previous reports on the characterization of ophthalmic ointments are very limited. Although there are FDA guidance documents and USP monographs covering some aspects of semisolid formulations, there are no FDA guidance documents nor any USP monographs for ophthalmic ointments. This review summarizes the physicochemical and in vitro profiling methods that have been previously reported for ophthalmic ointments. Specifically, insight is provided into physicochemical characterization (rheological parameters, drug content and content uniformity, and particle size of the API in the finished ointments) as well as important considerations (membranes, release media, method comparison, release kinetics and discriminatory ability) in in vitro release testing (IVRT) method development for ophthalmic ointments. Graphical Abstract Summary of the physicochemcial profiling and in vitro drug release testing (IVRT) for ophthalmic ointments.

Ophthalmic Drug Delivery Systems for Antibiotherapy-A Review.

The last fifty years, ophthalmic drug delivery research has made much progress, challenging scientists about the advantages and limitations of this drug delivery approach. Topical eye drops are the most commonly used formulation in ocular drug delivery. Despite the good tolerance for patients, this topical administration is only focus on the anterior ocular diseases and had a high precorneal loss of drugs due to the tears production and ocular barriers. Antibiotics are popularly used in solution or in ointment for the ophthalmic route. However, their local bioavailability needs to be improved in order to decrease the frequency of administrations and the side effects and to increase their therapeutic efficiency. For this purpose, sustained release forms for ophthalmic delivery of antibiotics were developed. This review briefly describes the ocular administration with the ocular barriers and the currently topical forms. It focuses on experimental results to bypass the limitations of ocular antibiotic delivery with new ocular technology as colloidal and in situ gelling systems or with the improvement of existing forms as implants and contact lenses. Nanotechnology is presently a promising drug delivery way to provide protection of antibiotics and improve pathway through ocular barriers and deliver drugs to specific target sites.

A Review on In Situ gel forming ophthalmic drug delivery systems

Nowadays ophthalmic route of administration of drugs is rapidly progressing and more studies are going on in formulating ophthalmic drug delivery systems. There are many conventional dosage forms available in the market like ointments, eye drops etc. The main drawback with these types of formulations is rapid drainage of the instilled dose due to the lacrimal fluid secretions and blinking of the eye lids. In order to minimize this drainage and to increase the ocular residence time and corneal contact time, in situ gel forming formulations are developed. In these systems sol to gel transformation takes place due to the environmental changes like pH, temperature, ionic strength. Some polymers like sodium alginate, HPMC are frequently used to initiate these processes. These formulations can be assessed for viscosity, clarity, gel strength, gelling capacity, gelling time, texture, isotonicity, sterility, ocular irritancy, anti-microbial efficacy, in vitro drug release, ex vivo release, in vivo absorption, in vivo retention and stability.

Applications of polymers in intraocular drug delivery systems.

We are entering a new era of ophthalmic pharmacology where new drugs are rapidly being developed for the treatment of anterior and posterior segment of the eye disease. The pharmacokinetics of drug delivery to the eye remains a very active area of ophthalmic research. Intraocular drug delivery systems allow the release of the drug, bypassing the blood-ocular barrier. The main advantage of these preparations is that they can release the drug over a long time with one single administration. These pharmaceutical systems are of great important in the treatment of the posterior segment diseases, and they can be prepared from biodegradable or nonbiodegradable polymers. Biodegradable polymers have the advantage of disappearing from the site of action after releasing the drug. The majority of intraocular devices are prepared from nonbiodegradable polymers, and they can release controlled amounts of drugs for months. Nonbiodegradable polymers include silicone, polyvinyl alcohol, and ethylene-vinyl acetate. The polymers usually employed to prepare nanoparticles for the topical ophthalmic route are poly (acrylic acid) derivatives (polyalquilcyanocrylates), albumin, poly-ε-caprolactone, and chitosan. Dendrimers are a recent class of polymeric materials with unique nanostructure which has been studied to discover their role in the delivery of therapeutics and imaging agents. Hydrogels are polymers that can swell in aqueous solvent system, and they hold the solvents in a swollen cross-linked gel for delivery. This review exhibits the current literature regarding applications of polymers in ophthalmic drug delivery systems including pharmacokinetics, advantages, disadvantages, and indications aimed to obtain successful eye therapy.Method of Literature Search:A systematic literature review was performed using PubMed databases into two steps. The first step was oriented to classification of intraocular polymers implants focusing on their advantages and disadvantages. The second step was focused on the role of polymers therapy for intraocular pathology with clinical examples. The search strategy was not limited by year of publication.

Ophthalmic atropine for sublingual use: A novel treatment for excessive respiratory secretions

We describe a novel case of utilizing ophthalmic atropine suspension via sublingual route to control excessive secretions in a critically ill patient. In addition, a medication event related to a labeling and administration event is described where the patient received the drug via ophthalmic route. A 32-year-old Hispanic female presenting with NMDA-receptor antibody mediated encephalitis experienced a prolonged intensive care unit (ICU) stay secondary to hypercarbic respiratory failure complicated by excessive respiratory secretions. After one week on mechanical ventilation, the patient was set to undergo a percutaneous endoscopic gastrostomy (PEG) tube placement and tracheotomy. The patient’s respiratory status was compromised by copious secretion production, preventing the patient from being transitioned to the general care floor. For secretion control, pharmacological interventions such as scopolamine transdermal patches and glycopyrrolate oral tablets were trialed, however systemic exposure to these agents resulted in urinary retention requiring catherization with a mild and persistent tachycardia. Ophthalmic atropine was administered sublingually at a dose of 1 mg every six hours to provide local relief of the patient's secretion production. Secretion production improved within 72 hours and the patient’s urinary retention resolved at the time of scopolamine and glycopyrrolate discontinuation. Previously in the literature the use of sublingual atropine was only described for secretion control in patients receiving end of life care, drug induced sialorrhea and neuro-developmental disorders. As observed in this case report, sublingual atropine may be an effective treatment to control respiratory secretions in critically ill patients who are unable to tolerate other therapies.

Organogels in Drug Delivery: A Special Emphasis on Pluronic Lecithin Organogels

Organogels have emerged as an alternative carrier for small and macromolecules via transdermal, oral, rectal and ophthalmic routes. Pluronic lecithin organogels (PLO gels) are lecithin-based organogels widely used in compounding pharmacies as a vehicle for enhancing the transdermal permeability of many therapeutic drugs. However, the scientific and systematic evidence in support of how well PLO gels help in transdermal delivery is scanty. Recently, some clinical studies have reported nearly complete lack of bioavailability of certain topically administered drugs from PLO gels. The present review aims at summarizing gels and organogels, with a focus on the use of PLO gels in transdermal drug delivery. A special emphasis is placed on controversies looming over the use of PLO gels as a delivery platform for drugs via transdermal route. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Organogels in Drug Delivery: A Special Emphasis on Pluronic Lecithin Organogels.

Organogels have emerged as an alternative carrier for small and macromolecules via transdermal, oral, rectal and ophthalmic routes. Pluronic lecithin organogels (PLO gels) are lecithin-based organogels widely used in compounding pharmacies as a vehicle for enhancing the transdermal permeability of many therapeutic drugs. However, the scientific and systematic evidence in support of how well PLO gels help in transdermal delivery is scanty. Recently, some clinical studies have reported nearly complete lack of bioavailability of certain topically administered drugs from PLO gels. The present review aims at summarizing gels and organogels, with a focus on the use of PLO gels in transdermal drug delivery. A special emphasis is placed on controversies looming over the use of PLO gels as a delivery platform for drugs via transdermal route.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Design and characterization of an ocular topical liposomal preparation to replenish the lipids of the tear film.

Dry eye (DE) includes a group of diseases related to tear film disorders. Current trends for DE therapy focus on providing lipid components to replace the damaged lipid layer. Formulations that contain aqueous and mucin-like compounds may have additional therapeutic benefits for DE patients. The aim of this work was to design and evaluate novel formulations having the potential to become topical treatment for DE. Unpreserved liposomal formulations composed of phosphatidylcholine (PC), cholesterol, and α-tocopherol (vit E) were prepared by the thin-film hydration technique. Formulations were characterized in terms of liposome size, pH, surface tension, osmolarity, and viscosity. In vitro tolerance assays were performed on macrophage, human corneal, and conjunctival cell lines at short- and long-term exposures. In vivo ocular tolerance was studied after instillation of the formulation. The mean liposome size was less than 1 μm and surface tension < 30 mN/m for all formulations. The final liposomal formulation (PC-cholesterol-vit E in a ratio of 8:1:0.8) had physiological values of pH (6.45 ± 0.09), osmolarity (289.43 ± 3.28 mOsm), and viscosity (1.82 ± 0.02 mPa · s). Cell viability was greater than 80% in the corneal and conjunctival cells. This formulation was well tolerated by experimental animals. The unpreserved liposomal formulation has suitable properties to be administered by a topical ophthalmic route. The liposome-based artificial tear had good in vitro and in vivo tolerance responses. This formulation, composed of a combination of liposomes and bioadhesive polymers, may be used successfully as a tear film substitute in DE therapy.

Poly(amidoamine) dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide

The purpose of this study was to determine the influence of a controlled incremental increase in size, molecular weight and number of amine, carboxylate and hydroxyl surface groups in several series of poly(amidoamine) (PAMAM) dendrimers for controlled ocular drug delivery. The duration of residence time was evaluated after solubilization of several series of PAMAM dendrimers (generations 1.5 and 2–3.5 and 4) in buffered phosphate solutions containing 2‰ (w/v) of fluorescein. The New Zealand albino rabbit was used as an in vivo model for qualitative and quantitative assessment of ocular tolerance and retention time after a single application of 25 μl of dendrimer solution to the eye. The same model was also used to determine the prolonged miotic or mydriatic activities of dendrimer solutions, some containing pilocarpine nitrate and some tropicamide, respectively. Residence time was longer for the solutions containing dendrimers with carboxylic and hydroxyl surface groups. No prolongation of remanence time was observed when dendrimer concentration (0.25–2%) increased. The remanence time of PAMAM dendrimer solutions on the cornea showed size and molecular weight dependency. This study allowed novel macromolecular carriers to be designed with prolonged drug residence time for the ophthalmic route.

Formulation and in vivo evaluation of ocular insert containing phenylephrine and tropicamide

A Gelfoam® based ocular device containing 1.7 mg of phenylephrine and 0.6 mg of tropicamide was formulated and evaluated for pupillary dilation in rabbits. The manufacturing procedure is fairly simple and the required excipients are inexpensive. The in vivo results show that the mydriatic response produced by the proposed device is larger and longer lasting than that produced by eyedrops with an equivalent amount of phenylephrine and tropicamide. The results reported in this study, along with those of previous studies, imply that Gelfoam® is a versatile drug carrier for either local or systemic drug delivery via the ophthalmic route.

In Vivo Evaluation of Dosage Forms: Application of Gamma Scintigraphy to Non-enteral Routes of Administration

The trend to deliver drugs to defined areas of the body involves sophisticated carriers systems. In addition to the in vitro drug release profile one must be aware of the in vivo behaviour of the dosage form and the drug. Gamma scintigraphy is an elegant way to gain insights of the actual in vivo distribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables the in vivo determination of the targeting of the formulation administered through a large number of routes. The present paper reviews applications of gamma scintigraphy for the evaluation of dosage forms administered by the parenteral, rectal, buccal, nasal, pulmonary, and ophthalmic routes.

Drug delivery systems

New and emerging drug delivery systems for traditional drugs and the products of biotechnology are discussed, and the role of the pharmacist in ensuring the appropriate use of these systems is outlined. Advantages of advanced drug delivery systems over traditional systems are the ability to deliver a drug more selectively to a specific site; easier, more accurate, less frequent dosing; decreased variability in systemic drug concentrations; absorption that is more consistent with the site and mechanism of action; and reductions in toxic metabolites. Four basic strategies govern the mechanisms of advanced drug delivery: physical, chemical, biological, and mechanical. Oral drug delivery systems use natural and synthetic polymers to deliver the product to a specific region in the gastrointestinal tract in a timely manner that minimizes adverse effects and increases drug efficacy. Innovations in injectable and implantable delivery systems include emulsions, particulate delivery systems, micromolecular products and macromolecular drug adducts, and enzymatic-controlled delivery. Options for noninvasive drug delivery include the transdermal, respiratory, intranasal, ophthalmic, lymphatic, rectal, intravaginal, and intrauterine routes as well as topical application. Rapid growth is projected in the drug delivery systems market worldwide in the next five years. Genetic engineering has mandated the development of new strategies to deliver biotechnologically derived protein and peptide drugs and chemoimmunoconjugates. The role of the pharmacist in the era of advanced drug delivery systems will be broad based, including administering drugs, compounding, calculating dosages based on pharmacokinetic and pharmacodynamic monitoring, counseling, and research. The advent of advanced drug delivery systems offers pharmacists a new opportunity to assume an active role in patient care.

Determination by coupled high-performance liquid chromatography—gas chromatography of the β-blocker levomoprolol in plasma following ophthalmic administration

Levomoprolol is a β-blocking agent used in the topical treatment of glaucoma. The necessity for comparing the plasma levels of a drug administered by the ophthalmic route with those obtained following systemic treatment requires increasingly sensitive methods in order to determine the low plasma concentrations produced by the administration of eye drops. On-line high-performance liquid chromatography-gas chromatography and concurrent solvent evaporation proved to be advantageous in the determination of levomoprolol in human plasma. Levomoprolol was determined by capillary gas chromatography ( GC) with electron-capture detection ( ECD) after solid-phase extraction from plasma and derivatization. Quantitation was based on the internal standard method. The detection limit of 0.2 ng/ml is 50 times lower than that obtained with previous GC methods involving on-column injection and ECD.