Recent advances in ocular drug delivery

Amongst the various routes of drug delivery, the field of ocular drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. Recent research has focused on the characteristic advantages and limitations of the various drug delivery systems, and further research will be required before the ideal system can be developed. Administration of drugs to the ocular region with conventional delivery systems leads to short contact time of the formulations on the epithelium and fast elimination of drugs. This transient residence time involves poor bioavailability of drugs which can be explained by the tear production, non-productive absorption and impermeability of corneal epithelium. Anatomy of the eye is shortly presented and is connected with ophthalmic delivery and bioavailability of drugs. In the present update on ocular dosage forms, chemical delivery systems such as prodrugs, the use of cyclodextrins to increase solubility of various drugs, the concept of penetration enhancers and other ocular drug delivery systems such as polymeric gels, bioadhesive hydrogels, in-situ forming gels with temperature-, pH-, or osmotically induced gelation, combination of polymers and colloidal systems such as liposomes, niosomes, cubosomes, microemulsions, nanoemulsions and nanoparticles are discussed. Novel ophthalmic delivery systems propose the use of many excipients to increase the viscosity or the bioadhesion of the product. New formulations like gels or colloidal systems have been tested with numerous active substances by in vitro and in vivo studies. Sustained drug release and increase in drug bioavailability have been obtained, offering the promise of innovation in drug delivery systems for ocular administration. Combining different properties of pharmaceutical formulations appears to offer a genuine synergy in bioavailability and sustained release. Promising results are obtained with colloidal systems which present very comfortable conditions of use and prolonged action.     

Ocular preparations: the formulation approach

The main aim of pharmacotherapeutics is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. This article reviews: [1] the barriers that decrease the bioavailability of an ophthalmic drug; [2] the objectives to be considered in producing optimal formulations; and [3] the approaches being used to improve the corneal penetration of a drug molecule and delay its elimination from the eye. The focus of this review is on the recent developments in topical ocular drug delivery systems, the rationale for their use, their drug release mechanism, and the characteristic advantages and limitations of each system. In addition, the review attempts to give various analytical procedures including the animal models and other models required for bioavailability and pharmacokinetic studies. The latter can aid in the design and predictive evaluation of newer delivery systems.

The dosage forms are divided into the ones which affect the precorneal parameters, and those that provide a controlled and continuous delivery to the pre- and intraocular tissues. The systems discussed include: (a) the commonly used dosage forms such as gels, viscosity imparting agents, ointments, and aqueous suspensions; (b) the newer concept of penetration enhancers, phase transition systems, use of cyclodextrins to increase solubility of various drugs, vesicular systems, and chemical delivery systems such as the prodrugs; (c) the developed and under-development controlled/continuous drug delivery systems including ocular inserts, collagen shields, ocular films, disposable contact lenses, and other new ophthalmic drug delivery systems; and (d) the newer trends directed towards a combination of drug delivery technologies for improving the therapeutic response of a non-efficacious drug. The fruitful resolution of the above-mentioned technological suggestions can result in a superior dosage form for both topical and intraocular ophthalmic application.     

Ocular Preparations: The Formulation Approach

ABSTRACT

The main aim of pharmacotherapeutics is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. This article reviews: the barriers that decrease the bioavailability of an ophthalmic drug; the objectives to be considered in producing optimal formulations; and the approaches being used to improve the corneal penetration of a drug molecule and delay its elimination from the eye. The focus of this review is on the recent developments in topical ocular drug delivery systems, the rationale for their use, their drug release mechanism, and the characteristic advantages and limitations of each system. In addition, the review attempts to give various analytical procedures including the animal models and other models required for bioavailability and pharmacokinetic studies. The latter can aid in the design and predictive evaluation of newer delivery systems.

The dosage forms are divided into the ones which affect the precorneal parameters, and those that provide a controlled and continuous delivery to the pre- and intraocular tissues. The systems discussed include: (a) the commonly used dosage forms such as gels, viscosity imparting agents, ointments, and aqueous suspensions; (b) the newer concept of penetration enhancers, phase transition systems, use of cyclodextrins to increase solubility of various drugs, vesicular systems, and chemical delivery systems such as the prodrugs; (c) the developed and under-development controlled/continuous drug delivery systems including ocular inserts, collagen shields, ocular films, disposable contact lenses, and other new ophthalmic drug delivery systems; and (d) the newer trends directed towards a combination of drug delivery technologies for improving the therapeutic response of a non-efficacious drug. The fruitful resolution of the above-mentioned technological suggestions can result in a superior dosage form for both topical and intraocular ophthalmic application.     

Ocular drug metabolism of the bioactivating antioxidant N-acetylcarnosine for vision in ophthalmic prodrug and codrug design and delivery

The basic idea in this study relates to the interesting research problem to employ with the knowledgeable pharmacy staff N-acetylcarnosine (NAC) in the developed suitable compounded prodrug ophthalmic preparations, which are currently used for the treatment of cataract and have antioxidant effect, in order to provide the molecular support to one of the most popular beliefs of the growing market for the treatment of senile cataract in patients and animals with efficacious NAC drug formulations worldwide patented by the author. This work presents the progress in ocular NAC prodrug and codrug design and delivery in light of revealed ocular metabolic activities. There is a considerable interest in the ophthalmic codrug design including NAC prodrug based on the strategies to improve ophthalmic drug delivery of the active peptide principal L-carnosine through the sustained intraocular metabolic activation of a dipeptide while making it resistant to enzymatic hydrolysis. Novel approaches to ocular NAC drug delivery, developed by Innovative Vision Products, Inc. (IVP), aim at enhancing the drug bioavailability by ensuring a prolonged retention of the medication in the eye, and/or by facilitating transcorneal penetration. IVP team studied the effects of lubricant eye drops designed as 1% NAC prodrug of L-carnosine containing a mucoadhesive cellulose-based and corneal absorption promoters in a drug delivery system. The predicted responses of the corneal and conjunctival penetrations to the synergistic promoters are useful in controlling the extent and pathway of the ocular and systemic absorptions of instilled NAC prodrug in designed ophthalmic formulations thereof. Utility of peptidase enzyme inhibitors in the codrug formulation to modulate the transport and metabolism of NAC prodrug appears to be a promising strategy for enhancing dipeptide drug transport across the cornea. The developed and officially CE mark registered by IVP NAC prodrug and codrug lubricating eye drop systems (including principal regulatory registered eye drops design and lubricating eye drops marketed under numerous brand labels), increase the intraocular uptake of the active principle L-carnosine from its ophthalmic carrier NAC in the aqueous humor and the permeability of a drug into the eye, and so enhance the ocular bioavailability, bioactivating universal antioxidant, and anti-cataract efficacy (in human and in canine eyes) of the developed NAC eye drops.     

Ocular Drug Metabolism of the Bioactivating Antioxidant N-acetylcarnosine for Vision in Ophthalmic Prodrug and Codrug Design and Delivery

The basic idea in this study relates to the interesting research problem to employ with the knowledgeable pharmacy staff N-acetylcarnosine (NAC) in the developed suitable compounded prodrug ophthalmic preparations, which are currently used for the treatment of cataract and have antioxidant effect, in order to provide the molecular support to one of the most popular beliefs of the growing market for the treatment of senile cataract in patients and animals with efficacious NAC drug formulations worldwide patented by the author.

This work presents the progress in ocular NAC prodrug and codrug design and delivery in light of revealed ocular metabolic activities. There is a considerable interest in the ophthalmic codrug design including NAC prodrug based on the strategies to improve ophthalmic drug delivery of the active peptide principal L-carnosine through the sustained intraocular metabolic activation of a dipeptide while making it resistant to enzymatic hydrolysis. Novel approaches to ocular NAC drug delivery, developed by Innovative Vision Products, Inc. (IVP), aim at enhancing the drug bioavailability by ensuring a prolonged retention of the medication in the eye, and/or by facilitating transcorneal penetration.

IVP team studied the effects of lubricant eye drops designed as 1% NAC prodrug of L-carnosine containing a mucoadhesive cellulose-based and corneal absorption promoters in a drug delivery system. The predicted responses of the corneal and conjunctival penetrations to the synergistic promoters are useful in controlling the extent and pathway of the ocular and systemic absorptions of instilled NAC prodrug in designed ophthalmic formulations thereof. Utility of peptidase enzyme inhibitors in the codrug formulation to modulate the transport and metabolism of NAC prodrug appears to be a promising strategy for enhancing dipeptide drug transport across the cornea.

The developed and officially CE mark registered by IVP NAC prodrug and codrug lubricating eye drop systems (including principal regulatory registered eye drops design and lubricating eye drops marketed under numerous brand labels), increase the intraocular uptake of the active principle L-carnosine from its ophthalmic carrier NAC in the aqueous humor and the permeability of a drug into the eye, and so enhance the ocular bioavailability, bioactivating universal antioxidant, and anti-cataract efficacy (in human and in canine eyes) of the developed NAC eye drops.     

Corneal permeability of ketorolac tromethamine when formulated with tobramycin

In vitro rabbit corneal penetration studies were designed to determine the effect tobramycin (an antibiotic) has on the diffusion of ketorolac tromethamine (a nonsteroidal anti-inflammatory compound). Evaluation was performed in two vehicle solutions: (1) a simple sodium chloride vehicle and (11) a suitable ophthalmic formulation. Quantitation of both ketorolac tromethamine and tobramycin were performed to determine the corneal penetration of each drug. Tobramycin was found to penetrate rabbit cornea to a limited extent. Also, tobramycin proved neither to impede nor enhance ketorolac's corneal diffusion. Both compounds showed greater penetration in an ophthalmic formulation, presumably due to the effects of the preservative, benzalkonium chloride (a quaternary ammonium compound)—known for disrupting corneal integrity.     

Corneal permeability of ketorolac tromethamine when formulated with tobramycin

Abstract

In vitro rabbit corneal penetration studies were designed to determine the effect tobramycin (an antibiotic) has on the diffusion of ketorolac tromethamine (a nonsteroidal anti-inflammatory compound). Evaluation was performed in two vehicle solutions: (1) a simple sodium chloride vehicle and (11) a suitable ophthalmic formulation. Quantitation of both ketorolac tromethamine and tobramycin were performed to determine the corneal penetration of each drug. Tobramycin was found to penetrate rabbit cornea to a limited extent. Also, tobramycin proved neither to impede nor enhance ketorolac's corneal diffusion. Both compounds showed greater penetration in an ophthalmic formulation, presumably due to the effects of the preservative, benzalkonium chloride (a quaternary ammonium compound)—known for disrupting corneal integrity.     

Ungual and transungual drug delivery

Topical therapy is desirable in treatment of nail diseases like onychomycosis (fungal infection of nail) and psoriasis. The topical treatment avoids the adverse effects associated with systemic therapy, thereby enhancing the patient compliance and reducing the treatment cost. However the effectiveness of the topical therapies has been limited due to the poor permeability of the nail plate to topically applied therapeutic agents. Research over the past one decade has been focused on improving the transungual permeability by means of chemical treatment, penetration enhancers, mechanical and physical methods. The present review is an attempt to discuss the different physical and chemical methods employed to increase the permeability of the nail plate. Minimally invasive electrically mediated techniques such as iontophoresis have gained success in facilitating the transungual delivery of actives. In addition drug transport across the nail plate has been improved by filing the dorsal surface of the nail plate prior to application of topical formulation. But attempts to improve the trans-nail permeation using transdermal chemical enhancers have failed so far. Attempts are on to search suitable physical enhancement techniques and chemical transungual enhancers in view to maximize the drug delivery across the nail plate.     

Contribution of the cornea and internal surfaces to the change of ocular aberrations with age.

We studied the age dependence of the relative contributions of the aberrations of the cornea and the internal ocular surfaces to the total aberrations of the eye. We measured the wave-front aberration of the eye with a Hartmann-Shack sensor and the aberrations of the anterior corneal surface from the elevation data provided by a corneal topography system. The aberrations of the internal surfaces were obtained by direct subtraction of the ocular and corneal wave-front data. Measurements were obtained for normal healthy subjects with ages ranging from 20 to 70 years. The magnitude of the RMS wave-front aberration (excluding defocus and astigmatism) of the eye increases more than threefold within the age range considered. However, the aberrations of the anterior corneal surface increase only slightly with age. In most of the younger subjects, total ocular aberrations are lower than corneal aberrations, while in the older subjects the reverse condition occurs. Astigmatism, coma, and spherical aberration of the cornea are larger than in the complete eye in younger subjects, whereas the contrary is true for the older subjects. The internal ocular surfaces compensate, at least in part, for the aberrations associated with the cornea in most younger subjects, but this compensation is not present in the older subjects. These results suggest that the degradation of the ocular optics with age can be explained largely by the loss of the balance between the aberrations of the corneal and the internal surfaces.     

Formulation of Penetration Enhancers in Polymers

Abstract

Two commercial polymer matrices were prepared : the hydrophilic macromolecular polyvinyl alcohol-povidone type and the hydrophobic microseal silastic silicone type. Different blends of the penetration enhancers Azone, 2-Pyrol and M-Pyrol in glycerine were incorporated with the drug, levodopa. The in-vitro dissolution of drug from these matrices and its diffusion through a semi-permeable membrane were measured. Results show that povidone polymers released 10 times more levodopa than did silicone polymers. The penetration enhancers significantly increased the rate of release of drug.     

Preparation and evaluation of a timolol maleate drug–resin ophthalmic suspension as a sustained-release formulation in vitro and in vivo

Abstract

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug–resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8?±?1.2?μm and drug loading at 43.00?±?0.09 %. The results indicate that drug released from the drug–resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug–resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.     

Ocular delivery systems for topical application of anti-infective agents

For the treatment of anterior eye segment infections using anti-infective agents, topical ocular application is the most convenient route of administration. However, topical delivery of anti-infective agents is associated with a number of problems and challenges owing to the unique structure of the eye and the physicochemical properties of these compounds. Topical ocular drug delivery systems can be classified into two forms: conventional and non-conventional. The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation resulting in low ocular bioavailability. Recently, attention has been focused on improving topical ocular delivery of anti-infective agents using advanced drug delivery systems. This review will focus on the challenges of efficient topical ocular delivery of anti-infective agents and will discuss the various types of delivery systems used to improve the treatment anterior segment infections.     

Corneal Critical Barrier against the Penetration of Dexamethasone and Lomefloxacin Hydrochloride: Evaluation by the Activation Energy for Drug Partition and Diffusion in Cornea

The cornea is a solid barrier against drug permeation. We searched the critical barrier of corneal drug permeation using a hydrophobic drug, dexamethasone (DM), and a hydrophilic drug, lomefloxacin hydrochloride (LFLX). The activation energies for permeability of DM and LFLX across the intact cornea were 88.0 and 42.1 kJ/mol, respectively. Their activation energies for permeability across the cornea without epithelium decreased to 33.1 and 16.6 kJ/mol, respectively. The results show that epithelium is the critical barrier on the cornea against the permeation of a hydrophobic drug of DM as well as a hydrophilic drug of LFLX. The activation energy of partition for DM (66.8 kJ/mol) was approximately 3-fold larger than that of diffusion (21.2 kJ/mol). The results indicate that the partition for the hydrophobic drug of DM to the corneal epithelium is the primary barrier. Thermodynamic evaluation of activation energy for the drug permeation parameters is a good approch to investigate the mechanism of drug permeability.     

Corneal critical barrier against the penetration of dexamethasone and lomefloxacin hydrochloride: evaluation by the activation energy for drug partition and diffusion in cornea

The cornea is a solid barrier against drug permeation. We searched the critical barrier of corneal drug permeation using a hydrophobic drug, dexamethasone (DM), and a hydrophilic drug, lomefloxacin hydrochloride (LFLX). The activation energies for permeability of DM and LFLX across the intact cornea were 88.0 and 42.1 kJ/mol, respectively. Their activation energies for permeability across the cornea without epithelium decreased to 33.1 and 16.6 kJ/mol, respectively. The results show that epithelium is the critical barrier on the cornea against the permeation of a hydrophobic drug of DM as well as a hydrophilic drug of LFLX. The activation energy of partition for DM (66.8 kJ/mol) was approximately 3-fold larger than that of diffusion (21.2 kJ/mol). The results indicate that the partition for the hydrophobic drug of DM to the corneal epithelium is the primary barrier. Thermodynamic evaluation of activation energy for the drug permeation parameters is a good approch to investigate the mechanism of drug permeability.     

Alginate microsphere-collagen composite hydrogel for ocular drug delivery and implantation

A composite collagen hydrogel containing protein encapsulated alginate microspheres was developed for ocular applications. Bovine serum albumin (BSA) served as a drug model. The composite hydrogel retained optical clarity and mechanical robustness of control hydrogels without microspheres. A sustained release of BSA was achieved during an 11-day period in neutral phosphate buffer. The composite hydrogel supported human corneal epithelial cell growth and had adequate mechanical strength and excellent optical clarity for possible use as therapeutic lens for drug delivery and/or use as corneal substitute for transplantation into patients who have corneal diseases.     

Ocular hazards of the colors used during the festival-of-colors (Holi) in India--malachite green toxicity

The objective of this study was to evaluate the nature of the colors used and their toxicity to the eye upon exposure to them during celebration of Holi (our festival-of-colors). Color powders and formulations were procured at random in and around Delhi during the festival. The green/bluish-green colors reported with the higher incidence of ocular toxicity were subjected for further evaluation. Eyewash fluid collected from the patients exposed to the colors was also subjected for analysis. This study was further extended to evaluate the corneal penetration of malachite green using goat cornea in perfusion chamber. In 16/18 color samples collected, malachite green or 4-[(4-dimethylaminophenyl)-phenyl-methyl]-N,N-dimethyl-aniline was detected at different concentrations. In the eyewash fluid of four patients, HPLC estimation confirmed the presence of malachite green at concentrations of 1.3, 0.18, 3.5 and 5.4 microg in 250 ml which was responsible for its reported toxicity. The in vitrotrans-corneal penetration studies did not show any detectable amount of malachite green in effluent fluid-in vitro tissue retention studies revealed that increasing the contact time increases tissue concentration. After 2 min of exposure, the tissue concentration was significantly higher. To conclude, malachite green was extensively used in our festival of Holi and has caused severe ocular irritation with epithelial defect upon exposure, though it did not penetrate through the cornea-further in vitro and in vivo studies are required on colors used in Holi.     

Modelling the gravitational sag of the cornea and the subsequent quality of the refracted image

This paper presents model asymmetries in the topography of the human cornea arising from linear gravitational distributions of the intraocular pressure. Equations for the corneal radius of curvature were used to provide an indication of the gravitational sag of the cornea when the head is in an upright position. In such case, corneal astigmatism is found along the optic axis of the eye. Ray paths inclined at a particular angle to the optic axis produce images (spot diagrams) which show a significant reduction in corneal astigmatism.     

RES‐loaded pegylated CS NPs: for efficient ocular delivery

The objective of this study is to develop resveratrol (RES) loaded polyethylene glycols (PEGs) modified chitosan (CS) nanoparticles (NPs) by ionic gelation method for the treatment of glaucoma. While increasing the concentration of PEG, the particle size and polydispersity index of the formulations increased. Entrapment efficiency and RES loading (RL) of NPs decreased while increasing PEG concentration. The in vitro release of NPs showed an initial burst release of RES (45%) followed by controlled release. Osmolality of formulations revealed that the prepared NPs were iso‐osmolar with the tear. Ocular tolerance of the NPs was evaluated using hen''s egg test on the chorioallantoic membrane and it showed that the NPs were non‐irritant. RES‐loaded PEG‐modified CS NPs shows an improved corneal permeation compared with RES dispersion. Fluorescein isothiocyanate loaded CS NPs accumulated on the surface of the cornea but the PEG‐modified CS NPs crossed the cornea and reached retinal choroid. RES‐loaded PEG‐modified CS NPs reduced the intra‐ocular pressure (IOP) by 4.3 ± 0.5 mmHg up to 8 h in normotensive rabbits. These results indicate that the developed NPs have efficient delivery of RES to the ocular tissues and reduce the IOP for the treatment of glaucoma.Inspec keywords: conducting polymers, nanoparticles, nanomedicine, drug delivery systems, particle size, nanofabrication, organic compounds, biomembranes, cellular biophysics, eye, vision defects, biological tissuesOther keywords: RES‐loaded pegylated CS NP, efficient ocular delivery, resveratrol loaded polyethylene glycol modified chitosan nanoparticles, ionic gelation method, glaucoma treatment, particle size, polydispersity index, entrapment efficiency, RES loading, PEG concentration, in vitro release, osmolality formulations, ocular tolerance, hen egg testing, chorioallantoic membrane, improved corneal permeation, RES dispersion, fluorescein isothiocyanate loaded CS NP, cornea surface, reached retinal choroid, intraocular pressure, normotensive rabbits, RES delivery, ocular tissues     

Development of the loratadine gel for enhanced transdermal delivery

Background: The oral administration of loratadine, an antihistamine, can have a variety of adverse side effects, such as headache, fatigue, and nausea, because of the transient high blood concentration. To avoid these effects, loratadine can be administered using a transdermal drug delivery system. Method: This study examined the effects of the drug concentration on drug release from prepared hydroxypropyl methylcellulose gels using a synthetic cellulose membrane at 37°C. The drug concentrations tested were 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% (w/w). The effect of temperature on drug release from the 0.3% loratadine gels was evaluated at 27°C, 32°C, 37°C, and 42°C. Various types of penetration enhancers, such as glycols, glycerides, propylene glycol derivatives, nonionic surfactants, and fatty acids, were incorporated in the gel formulation to increase the level of drug permeation. Results: The rate of drug release increased with increasing drug concentration or temperature. The activation energy for the release of the drug was 5.714 kcal/mol for 0.3% loratadine gel. Among all the enhancers used in this study, polyoxyethylene 2-stearyl ether showed the best enhancing effect. The enhancement factor of the loratadine gel containing the polyoxyethylene 2-stearyl ether was 2.03 compared with that of the loratadine system containing no enhancer. Conclusions: These results suggest that the topical gel formulation of loratadine containing a penetration enhancer could be developed to enhance the penetration of loratadine.     

The effect of skin penetration enhancers on the transdermal delivery of pyridostigmine bromide

In vitro skin penetration studies of pyridostigmine bromide through human cadaver skin were conducted using a diffusion cell with constant hydrodynamic conditions. The results indicate that the drug penetrates poorly through human cadaver skin. However, skin penetration enhancers such as sodium oleate, sodium lauryl sulfate, n-decyl methyl sulfoxide, and N,N-dimethyldodecylamine-N-oxide substantially enhanced the permeability coefficient of the drug through human cadaver skin. The penetration enhancement of pyridostigmine bromide could be due to increased partitioning of the drug in the skin or due to the decreased tortuosity of the porous pathway in the stratum corneum.