Ocular Inserts Research Articles

Mucoadhesive ocular insert based on thiolated poly(acrylic acid): development and in vivo evaluation in humans

The aim of the study was to develop a mucoadhesive ocular insert for the controlled delivery of ophthalmic drugs and to evaluate its efficacy in vivo. The inserts tested were based either on unmodified or thiolated poly(acrylic acid). Water uptake and swelling behavior of the inserts as well as the drug release rates of the model drugs fluorescein and two diclofenac salts with different solubility properties were evaluated in vitro. Fluorescein was used as fluorescent tracer to study the drug release from the insert in humans. The mean fluorescein concentration in the cornea/tearfilm compartment as a function of time was determined after application of aqueous eye drops and inserts composed of unmodified and of thiolated poly(acrylic acid). The acceptability of the inserts by the volunteers was also evaluated. Inserts based on thiolated poly(acrylic acid) were not soluble and had good cohesive properties. A controlled release was achieved for the incorporated model drugs. The in vivo study showed that inserts based on thiolated poly(acrylic acid) provide a fluorescein concentration on the eye surface for more than 8 h, whereas the fluorescein concentration rapidly decreased after application of aqueous eye drops or inserts based on unmodified poly(acrylic acid). Moreover, these inserts were well accepted by the volunteers. The present study indicates that ocular inserts based on thiolated poly(acrylic acid) are promising new solid devices for ocular drug delivery.

Readability of ocular medication inserts.

To determine the readability of ocular medication inserts and whether they are an appropriate source of medication information for patients. The Flesch-Kincaid and SMOG readability formulas were used to calculate the readability of 10 common glaucoma medication inserts (Alphagan, Azopt, Betoptic, Betimolol, Cosopt, Optipranolol, Rescula, Trusopt, Timoptic, and Xalatan) and 6 widely used nonglaucoma medication inserts (Alrex, Lotemax, Ocuflox, Patanol, Pred Forte, and Zaditor). The 10 glaucoma medication inserts surveyed required an average overall grade level of 12.9 +/- 0.6 by the Flesch-Kincaid Index and of 13.5 +/- 0.6 by the SMOG formula. The 6 nonglaucoma medication inserts had an overall grade level of 11.1 +/- 0.6 by the Flesch-Kincaid Index and of 11.7 +/- 0.9 by the SMOG formula. All medications reviewed were above the eighth-grade level recommended by the Flesch-Kincaid Index for public materials. Ocular medication inserts are too complex to be an adequate source of medication information for the average American adult. This study highlights the need for improving communication and education regarding patients' medications.

Ophthalmic Delivery of Ciprofloxacin Hydrochloride from Different Polymer Formulations: In Vitro and In Vivo Studies

Reservoir-type ocular inserts were fabricated using sodium alginate containing ciprofloxacin hydrochloride as the core (drug reservoir) that was sandwiched between the Eudragit and/or polyvinylacetate films. Ocular inserts were packaged in aluminium foil and sterilized by gamma radiation. These were tested for sterility as per British Pharmacopoeia (BP). Ocular inserts were evaluated for in vitro release rate studies, microbial efficacy, in vivo release studies, efficacy against induced bacterial conjunctivitis in rabbit's eyes, concentration in the aqueous humor, and stability studies as per the International Conference on Harmonization (ICH) guidelines. Ocular inserts passed the test for sterility. They showed zero-order release of the drug in the in vitro and in vivo release studies over a period of 120 hr. The drug was found to be active against selected microorganisms as was proved by microbial efficacy studies. A high correlation coefficient was found between in vitro and in vivo release rate studies. Better improvement was observed in artificially induced bacterial conjunctivitis in rabbit's eyes, compared with marketed eye drops and placebo. Drug concentration in the aqueous humor was found above Minimum Inhibitory Concentration (MIC-90) against selected microorganisms. Shelf-life of the product was found to be more than 2 years.

Effect of chitosan on in vitro release and ocular delivery of ofloxacin from erodible inserts based on poly(ethylene oxide)

The effects of chitosan hydrochloride (CH–HCl) on in vitro release of ofloxacin (OFX) from mucoadhesive erodible ocular inserts and on the relevant ocular pharmacokinetics have been studied both to contribute evidence of the ability of CH–HCl to enhance transcorneal penetration of drugs and to increase the therapeutic efficacy of topically applied OFX. Circular inserts of 6 mm in diameter, 0.8–0.9 mm in thickness and 20 mg in weight, medicated with 0.3 mg drug, were prepared by powder compression. The addition of 10, 20 or 30% medicated CH–HCl microparticles, obtained by spray-drying, to formulations based on poly(ethylene oxide) of MW 900 kDa (PEO 900) or 2000 kDa (PEO 2000) produced changes in the insert microstructure which accelerated both insert erosion and OFX release from inserts. The effect was stronger with higher CH–HCl fractions. Of the CH–HCl-containing formulations based on either PEO 900 or PEO 2000, PEO 900–CH–HCl (9:1 w/w) was more suitable for a prolonged OFX release. Following insertion in the lower conjunctival sac of the rabbit's eye, such an insert produced no substantial increase of AUC eff (AUC in the aqueous humour for concentrations >MIC 90%) with respect to inserts based on plain PEO; however, it produced a concentration peak in the aqueous significantly higher than that produced by any of the CH–HCl-free PEO inserts, and well higher than the MIC 90% for the more resistant ocular pathogens (7 μg/ml vs. 4 μg/ml). It has been argued that the increase was due to the ability of CH–HCl to enhance the transcorneal permeability of the drug.

A study of release mechanisms of different ophthalmic drugs from erodible ocular inserts based on poly(ethylene oxide)

When topical controlled delivery of ophthalmic drugs is realised via erodible inserts, drug bioavailability is maximised, if release is controlled exclusively by insert erosion, since parallel mechanisms which increase the release rate, also increases the dose fraction cleared from the precorneal area by tear fluid draining. The respective contributions of diffusion and erosion to the release mechanism of different drugs, namely, prednisolone (PDS), oxytetracycline hydrochloride (OTH) and gentamicin sulfate (GTS), from erodible ocular inserts based on poly(ethylene oxide) (PEO) of molecular weight 400 or 900 kDa was determined by an in vitro technique adequate to predict the release mechanism in vivo. PDS and OTH were released with erosion-controlled kinetics. With therapeutic doses of these drugs in the inserts (0.3 mg, 1.5%), the possibility of a purely erosive mechanism was shown to rely upon drug–PEO molecular interactions, which limit drug diffusion in the swollen matrix. This was the case with OTH, for which strong interactions with PEO were measured, whereas some contribution from the parallel diffusive mechanism was evidenced for PDS, which showed weaker interactions with polymer. Such a contribution disappeared when the PDS concentration in the insert was increased to 6%, which suggested that the erosive mechanism is favoured by a drug concentration in the hydrated insert substantially higher than solubility. On the other hand, the release of about 50% GTS dose was controlled by diffusion, due to the high water solubility of this drug, accompanied by weak drug–PEO interactions. In this case the residence time of drug in the precorneal area is expected to be significantly shorter than that of the PEO carrier.

Ocular Preparations: The Formulation Approach

ABSTRACTThe 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.

Relevance of polymer molecular weight to the in vitro/in vivo performances of ocular inserts based on poly(ethylene oxide)

A previous study of the present authors on gel-forming erodible inserts, based on high molecular weight (MW, 400 kDa) poly(ethylene oxide) (PEO), for ocular controlled delivery of ofloxacin (OFX) has been extended to investigate the effects of PEO MW, in the 200–2000 kDa range, on insert properties relevant to therapeutic efficacy. Mucoadhesion has shown a dependence on MW, with a maximum for PEO 400. The in vitro drug release from inserts based on PEO 200, PEO 400 and PEO 900 was mainly controlled by insert erosion, whereas with PEO 2000 it was mainly diffusion-controlled in a first phase, followed by an erosion-controlled phase. The erosion time scale depended directly on MW. Immediately after application in the lower conjunctival sac of the rabbit eye, the inserts based on PEO of whichever MW formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. PEO 2000 was unsuitable as an insert material, since the resulting gel spilled from the eye, due to excessive swelling. The gel residence time in the precorneal area, the drug permanence time in the aqueous humor at concentrations >MIC and the time to reach the maximal drug concentration in the aqueous humor ( C max) depended directly on MW, indicating that transcorneal absorption was governed by gel erosion. All inserts increased C max and AUC eff (AUC for concentrations >MIC) with respect to the commercial eyedrops. The increases caused by PEO 400 and PEO 900 were similar (3.78- and 3.16-fold, respectively, for C max; 11.06- and 12.37-fold, respectively, for AUC eff), whereas smaller increases were produced by PEO 200. The PEO 400 and PEO 900 inserts have shown a potential for a topical treatment of endophthalmitis.

Stability indicating HPTLC determination of timolol maleate as bulk drug and in pharmaceutical preparations

Timolol was the first β blocker to be used as an anti-glaucoma agent and to date remains as the standard because none of the newer β blockers were found to be more effective. The high performance thin layer chromatographic method of analysis of timolol maleate is reported. The mobile phase selected was ethyl acetate–methanol–isopropyl alcohol–ammonia (25%) (80:20:2:1, v/v/v/v). The calibration curve of the drug was linear in the range of 100–600 ng. The spectrodensitometric analysis was carried out at 294 nm. The mean (±RSD) values of slope, correlation coefficient and intercept were 2487.5 (±0.9), 0.996 (±0.081) and 90463 (±1.1), respectively. The system precision and the method precision were excellent with an RSD of 2.8 and 1.004, respectively. The limits of detection and quantitation were 10 and 40 ng, respectively. The mean percent recovery was found to be 98.6. Timolol maleate was degraded by exposing the drug to heat, acid and base. The degraded products were found to be well separated from the pure drug with significantly different R f values suggesting a stability indicating analysis method for quantification of timolol maleate in pharmaceutical preparations and as bulk drug. The method was utilized to analyze timolol maleate from conventional eye drops and novel sustained release solid polymeric ocular inserts and oral preparations. The reported method is simple, selective, precise, accurate, time saving and economic as compared to reported HPLC methods.

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.

Feasibility of an In Vitro Microbiological Model as an Alternative to the Rabbit Eye Model

Ocular inserts of gentamicin sulfate with polyvinyl alcohol (PVA) 1.5%, 2.0%, and 2.5% and a combination of methyl cellulose 2% and Eudragit NE 30D 30%, 35%, and 40% w/w of methyl cellulose were fabricated by a casting technique. The inserts were sterilized by gamma radiation at 25 kGy and tested for sterility. The microbiological efficacy of the ocular inserts against Staphylococcus aureus ATCC 6538P and Pseudomonas aeruginosa NCIM 2200 was evaluated by developing an in vitro microbiological model and an in vivo noninvasive rabbit eye model. Parameters of the in vitro microbiological model were varied, and the results correlated with a noninvasive rabbit eye model. The in vitro model proved to be a viable alternative to the rabbit eye model in evaluating the microbiological efficacy of gentamicin sulfate ocular inserts.

Roles of acid/base nature and molecular weight in drug release from matrices of gelfoam and monoisopropyl ester of poly(vinyl methyl ether–maleic anhydride)

Ophthalmic drug inserts are usually placed in the conjunctival sac. Being in contact with the conjunctiva, they may provide means to deliver large and hydrophilic molecules, such as peptides and oligonucleotides into the eye. We evaluated Gelfoam and monoisopropyl ester of poly(vinyl methyl ether/maleic anhydride) (PVM/MA) as potential polymers for ocular inserts. Matrices were solvent cast with model drugs that had different p K a, molecular weight and hydrophilicity. Drug release from the matrices as well as charge and swelling of Gelfoam®-matrix were studied. The release of drugs from PVM/MA-matrices was by erosion of the polymer matrix. The molecular weight and other variants of the releasing compound did not affect their release. In Gelfoam®-matrices the release was diffusion controlled and it was affected by the pH of the external solution as well as the charge and molecular weight of the studied compound.

Optimized release of dexamethasone and gentamicin from a soluble ocular insert for the treatment of external ophthalmic infections

In the case of external ophthalmic infections, repeated instillations of antibiotics are required to reach therapeutic level, above the minimal inhibitory concentration (MIC). An additional administration of a corticosteroid is often needed, in order to limit the precorneal damages caused by the infection. However, repeated administration of a corticosteroid can increase intraocular pressure and thus lead to glaucoma. To overcome the disadvantages of separated and repeated instillations of two products and to avoid the side effects of dexamethasone, a soluble insert containing gentamicin sulfate and dexamethasone phosphate was developed. The new system ensures the concomitant release of the two drugs during the first 10 h of treatment, followed by an adequate concentration of gentamicin sulfate, above the MIC of 4.0 μg ml −1, during 50 h, due to a combination of gentamicin sulfate with cellulose acetate phthalate, which reduces the solubility of gentamicin.

Effect of Brij-78 on Systemic Delivery of Insulin from an Ocular Device

An ocular insert is developed for the controlled systemic delivery of insulin. Commercially available Gelfoam absorbable gelatin sponge, USP, is used in the fabrication of the ocular insert in the form of a matrix system. Two eyedrop formulations and 13 eye device formulations were evaluated. The efficacy of insulin ocular delivery was quantitated by monitoring the changes in its pharmacological response (i.e., blood glucose lowering). The in vivo results from devices containing 0.5 or 1.0mg of insulin with 20 µg of polyoxyethylene-20-stearyl ether (Brij-78) give a substantial improvement in insulin activity and a significant prolongation in its duration compared with the eyedrops. In addition, the mean blood glucose concentration returns to nearly normal levels within 60min after the removal of the device. Overall, the application of the Gelfoam device makes it feasible to obtain a prolonged systemic delivery of insulin within the desired therapeutic levels without the risk of hypoglycemia.‡

Pharmacokinetic Differences Between Ocular Inserts and Eyedrops

Controlled release ocular inserts have been found to increase the amount of drug which is absorbed into the aqueous humour when compared to eyedrops. Systemic absorption following delivery using a controlled release insert has been found to be dependent on the release rate of the insert. The objective of this study was to determine if ocular inserts affect drug absorption into other ocular tissues such as the conjunctiva and iris-ciliary body. Ocular absorption studies were performed using albino rabbits and ethylene-vinyl acetate controlled release devices containing timolol maleate. A compartmental model previously developed to simulate ocular absorption following eyedrop administration was modified and used to simulate these experiments. The conjunctival absorption coefficient calculated by the model and the AUC of the conjunctiva per mumol of delivered drug were found to be 2.7 and 42 times higher, respectively, for the ocular insert as compared to eyedrop administration. The increased conjunctiva absorption was likely the result of reduced tear mixing, which caused a high local concentration of timolol between the insert and the conjunctiva. The AUC of the iris-ciliary body per mumol of delivered drug was found to be 24 times higher for the ocular inserts as compared to eyedrop administration. The AUC of the iris-ciliary body was found to be 1.4 times higher than the AUC of the aqueous humour for eyedrop administration, but 9 times greater for delivery via the ocular inserts. Thus, the increased absorption into the iris-ciliary body and aqueous humour observed for ocular inserts is partially the result of an increase in the amount of drug which enters these tissues via penetration across the conjunctiva and sclera.

Influence of Drug Release Rate on Systemic Timolol Absorption from Polymeric Ocular Inserts in the Pigmented Rabbit

There is an expectation that ocular inserts, regardless of the nature of the polymer, will faithfully reduce systemic drug absorption. This may not necessarily be so, however, since not all polymers would release drug at the same rate and to the same extent. The objective of the present study was to determine how drug release rate from various polymeric ocular inserts may influence systemic timolol absorption in the pigmented rabbit. The inserts tested were made of polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), or partial ethyl ester of poly(vinyl methyl ether/maleic anhydride) (PVMMA), approximately 89.4% w/w in all cases. Some polyvinyl alcohol inserts contained timolol in salt form with Carbopol 940 (PVA-C940), 8.6% w/w. The time course of timolol in plasma over 6 hr was monitored using reversed phase HPLC. While all inserts reduced the peak timolol concentration in plasma (Cmax), only the PVA and HPC inserts, which released timolol rapidly in vitro, reduced the extent of systemic timolol absorption (AUC). On the other hand, both PVA-C940 and PVMMA inserts, which released timolol relatively slowly in vitro, increased the extent of systemic timolol absorption. Moreover, the time at which peak timolol concentration was achieved in the plasma was much delayed, raising the possibility of delayed timolol absorption until discharge of the presumably viscous and/or mucoadhesive solutions of PVA-C940 and PVMMA inserts into the nasal cavity. It may be concluded that not all polymeric ocular inserts reduce systemic timolol absorption. Whether an insert would do so depends on the interplay of residence time in the conjunctival sac and rate of drug release from the insert.

Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans.

Timolol eyedrops may cause systemic side-effects in glaucoma patients due to absorption of the drug into systemic circulation. In a previous study, timolol concentrations in plasma were reduced if timolol was administered in ocular inserts instead of eyedrops. We compared the intraocular pressure lowering effect and systemic absorption of timolol inserts to those of 0.5% timolol eyedrops in humans. Inserts of silicone tubing released 90.3 +/- 13.9 micrograms of timolol in 24 hours in vivo. Timolol inserts afforded similar decreases in intraocular pressure in open-angle glaucoma patients as did b.i.d. eyedrops, but produced lower peak timolol concentrations in plasma, 0.70 +/- 0.10 ng/ml and 0.24 +/- 0.05 ng/ml, respectively. After eyedrops, peak concentrations were achieved at 15.0 +/- 2.2 min, while application of an insert resulted in a delayed peak (tmax = 623 +/- 195 min). The insert resulted in a higher systemically absorbed fraction of the timolol dose than the eyedrop, but the peak timolol concentration and daily absorbed amount of timolol were decreased. The release rate of timolol from the inserts in vivo was only slightly less than that in vitro. Silicone devices are useful for clinical testing of controlled delivery properties of ocular drugs.

Modification of ocular and systemic absorption of timolol from ocular inserts by a buffering agent and a vasoconstrictor

Alkyl monoesters of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) are promising bioerodible polymers for controlling drug release. The dissolution of these polymers and drug release from them are highly dependent on the pH on the polymer surface. In this study, we examined the effects of disodium phosphate buffer on in vivo release, and on ocular and systemic absorption of timolol given in matrices of monoisopropyi ester of PVM-MA ocularly in rabbits. The vasoconstrictor methaoxedrine was added to some matrices to reduce the systemic absorption of timolol. Timolol concentrations in tear fluid and plasma were measured using a radioreceptor assay. [ 3H]Timolol-labeled matrices were used to study ocular absorption of timolol. The unbuffered matrix yielded a lower peak concentration of timolol in tear fluid (64 ± 9 (S.E.) μg/ml) and a lower steady-state concentration (1.0 ± 0.1 ng/ml) in plasma 3 h later than the buffered one (C max, tear fluid = 104 ± 8 μg/ml: C max , plasma = 7.3 ± 1.1 ng/ml). Thus, disodium phosphate increases the rate of timolol release from the inserts several fold in tear fluid. Co-administration of methaoxedrine in buffered matrices decreased the peak timolol concentration in plasma about 3-times and increased that in tear fluid about 2-fold. In iris-ciliary body, administration of buffered matrices resulted in timolol concentrations that were comparable with the levels after eye drop instillation. Compared to the unbuffered matrices, disodium phosphate without or with methaoxedrine at least doubled the concentration ratio of iris-ciliary body to plasma. The best iris-ciliary body/plasma concentration ratios were achieved with the buffered matrices containing methaoxedrine. Conjunctival and nasal vasoconstriction by methaoxedrine improves the ocular to systemic concentration ratio of timolol several fold. Compared to eye drops timolol administration in the inserts reduced the systemic β-blocking activity significantly.

Diagnosis and treatment of keratoconjunctivitis sicca in the dog.

Keratoconjunctivitis sicca (KCS) is a relatively common eye disease in the dog. The diagnosis is discussed, particularly of the early or mild case. The various types of medical treatment are described, including replacement therapy with artificial tears and ocular inserts, as well as other preparations; lacrimogenics; and other forms of medical treatment, including antibiotics, corticosteroids, mucolytics and hormones. Contraindicated drugs and agents are listed. Surgical treatments, including punctal occlusion, tarsorrhaphy, conjunctival flaps, contact lenses, superficial keratectomy, as well as parotid duct transposition, are discussed and the procedure indicated which is best suited to the case. The choice of treatment according to the severity of the KCS is also given.

The release of insoluble antibiotics from collagen ocular inserts in vitro and their insertion into the conjunctival sac of cattle

The release rate of procaine penicillin, erythromycin and erythromycin estolate from soluble and insoluble collagen films was investigated in vitro to develop an ocular insert for the treatment of infectious bovine keratoconjunctivitis. The release rate and duration of release varied according to the selection of antibiotic and vehicle. The combination of erythromycin estolate and soluble collagen produced the most sustained drug-delivery system. However, due to the inappropriate physical properties of collagen and poor retention of ocular inserts, it was considered that the development of an antibiotic-impregnated collagen ocular insert requires further investigation.

The use of plastic rings to determine the dimensions of ocular inserts for insertion into the conjunctival sac of cattle.

The use of plastic rings to determine the dimensions of ocular inserts for insertion into the conjunctival sac of cattle.