Multidose Preservative Free Eyedrops by Selective Removal of Benzalkonium Chloride from Ocular Formulations.

PURPOSE: About 70% of eye drops contain benzalkonium chloride (BAK) to maintain sterility. BAK is an effective preservative but it can cause irritation and toxicity. We propose to mitigate ocular toxicity without compromising sterility by incorporating a filter into an eye drop bottle to selectively remove BAK during the process of drop instillation. METHODS: The filter is a packed bed of particles made from poly(2-hydroxyethyl methacrylate) (pHEMA), which is a common ophthalmic material. We showed that pHEMA particle prepared by using ethoxylated trimethylolpropane triacrylate as crosslinker can be incorporated into a modified eyedrop bottle tip to selectively remove the preservative as the formulation is squeezed out of the bottle. Hydraulic permeability of the plug is measured to determine the resistance to eye drop squeezing, and % removal of BAK and drugs are determined. RESULTS: The modified tip has a hydraulic permeability of about 2 Darcy, which allows eyedrops formulations to flow through without excessive resistance. The tip is designed such that the patients can create an eyedrop of solution of 1-10 cP viscosity in 4 s with a nominal pressure. During this short contact time, the packed particles removed nearly 100% of benzalkonium chloride (BAK) from a 15 mL, 0.012% BAK solution but have only minimal impact on the concentration of contained active components. CONCLUSION: Our novel design can eliminate the preservative induced toxicity from eye drops thereby impacting hundreds of millions of patients with chronic ophthalmic diseases like glaucoma and dry eyes.

Hybrid Electrospun Polycaprolactone Mats Consisting of Nanofibers and Microbeads for Extended Release of Dexamethasone.

PURPOSE: We designed electrospun polycaprolactone mats consisting of nanofibers and microbeads for extended delivery of dexamethasone. METHODS: Thin flexible dexamethasone loaded polycaprolactone mats were prepared by electrospinning. The solvents, polymer loading, voltage and tip-to-collector distance were varied to explore the effects on microstructure of the mats. The microstructure was determined by scanning electron microscope imaging; drug transport was measured and modeled, and X-ray diffraction was used to gauge the crystallinity. Drug transport and X-ray diffraction studies were also conducted with a spin cast film for comparison. RESULTS: Thin mats, about 10 µm in thickness, were prepared by electrospinning. By controlling the voltage and tip-to-collector distance, we achieved a hybrid structure comprising of nanorods (nanofibers) and microbeads. The release profiles were fitted to the diffusion equation to obtain the diffusivities in the spheres and the rods. The diffusivity in the electrospun nanofibers was significantly lower compared to the casted films due to increased crystallinity, which was estimated from X-ray diffraction analysis. The electrospun hybrid mats sustained drug release for the desired duration of a month, in spite of the small thickness of about 10 µm. By comparison, a ten-fold thicker cast film sustains release for about the same duration suggesting about 100-fold decrease in diffusivity in the electrospun mats due to increased crystallinity. CONCLUSIONS: Electrospun polycaprolactone mats are optimal for achieving long release durations due to increased crystallinity. Designing a hybrid structure by controlling the electrospinning parameters can be a useful approach to increase the release durations.

Photoprotection and Extended Drug Delivery by UV Blocking Contact Lenses.

PURPOSE: Extended release of photo-unstable drugs from ophthalmic inserts is not useful unless the loaded drug is protected from degradation. Because of the recent interest in extended drug delivery from contact lenses, it is critical to assess whether photo-unstable drugs can be stabilized by loading in lenses. Here, we focus on dexamethasone, which is prone to degradation and has been explored as a candidate for extended release from contact lenses for periods ranging from 10 hours to several days. METHODS: Degradation rates of dexamethasone were measured in phosphate-buffered saline and after loading in contact lenses. The degradation rates were measured in a humidified, constant-temperature (32°C) chamber with controlled UV exposure. Contact lenses with various degrees of UV blocking were used to explore the relationship between degradation rates and UV exposure. It is known that vitamin E absorbs UV radiation; thus, it was loaded into the lenses to explore the feasibility of reducing the degradation rates. RESULTS: About 85% of dexamethasone degraded in 20 hours in non-UV blocking lenses, whereas less than 1% degraded in class 1 UV blocking lenses. Incorporation of vitamin E into the non-UV blocking lenses reduced the fractional degradation to 30%. Degradation rates in phosphate-buffered saline were significantly higher than even in non-UV blocking contact lenses. CONCLUSIONS: The degradation of dexamethasone can be minimized by using a UV blocking contact lens or incorporating vitamin E into a non-UV blocking lens. Vitamin E incorporation has the dual benefits of improving drug stability and release profiles.

The challenging management of Moebius syndrome using orthodontic camouflage: A case report.

Moebius syndrome (MS) is a rare congenital neuromuscular disorder characterized by weakness or paralysis (palsy) of abducens and facial nerves, or other cranial nerves which may be affected. Diagnosis, treatment, and dental management of MS patients are focused on treating manifestations like malocclusion, while catering to associated extraoral (neurologic, dermatologic, ocular) complications, aiming to improve their quality of life. Here, we report the case of a 9-year-old female patient with MS who underwent orthodontic camouflage using combined orthopedic-orthodontic therapy using a high-pull chin cup and fixed orthodontic appliance to improve skeletal mal-relation and facial appearance. The outcome displayed great improvement in function and better esthetics, improving not only the patient's but also the family's quality of life. A year's follow-up showed successful maintenance of the achieved results. A multidisciplinary approach in MS not only helps in overcoming the treatment challenges but also provides great psychosocial benefits to these patients.

Sustained release of inactivated H1N1 virus from degradable microparticles for extended vaccination.

Influenza vaccines administered as intramuscularly injected inactivated viruses or intranasally administered live-attenuated viruses usually provide short-term protection against influenza infections. Biodegradable particles that provide sustained release of the antigen has been studied as an approach to extend vaccine protection. Here, we investigate sustained release of ultraviolet killed influenza A virus (A/PR/8/34(H1N1)) (kPR8) loaded into poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles. Particles were prepared using the double emulsion method, and polymer molecular weight (MW), polymer hydrophobicity, polymer concentration in the organic phase, and the amount of killed virus were varied to obtain a range of particles. Formulations included PLGA 50:50 (2-6, 7-17 kDa), PLGA 75:25 (4-15 kDa), and 50/50 PLGA 75:25 (4-15 kDa)/PCL (14 kDa). Additionally, NaOH was co-encapsulated in some cases to enhance particle degradation. The structure of the particles was explored by size measurements and electron microscopy. The kPR8 release profiles were measured using hemagglutinin ELISA. The concentration of the polymer (PLGA) in the organic phase and polymer MW significantly influenced virus loading, while polymer MW and co-encapsulation of NaOH modulated the release profiles. Mice receiving a single intramuscular injection of NaOH microparticle-encapsulated kPR8 were partially protected against a lethal influenza challenge 32 weeks post immunization. Microparticle (MP) vaccination induced a gradual increase in PR8-specific IgGs dominated by IgG1 in contrast to the rapid IgG2a-biased response elicited by soluble kPR8 immunization. Our results indicate that vaccine-NaOH co-loaded PLGA particles show potential as a single dose vaccination strategy for extended protection against influenza virus infection.

Sustained release system from PLGA particles co-encapsulated with inactivated influenza virus with natural killer T cell agonist α-galactosylceramide.

Vaccines against influenza and many other infectious diseases require multiple boosters in addition to the primary dose to improve efficacy, but this approach is not ideal for compliance. The multiple doses could potentially be replaced by sustained or pulsatile release of antigens encapsulated in degradable microparticles (MPs). The efficacy of a vaccine is improved by adding an adjuvant, which can be co-delivered from the particles to enhance immunogenicity. Here, we developed degradable poly-lactic-co-glycolic acid (PLGA) (7-17 kDa) MPs capable of sustained release of ultraviolet killed influenza virus (A/PR/8/34) (kPR8) vaccine and the natural killer T (NKT) cell agonist alpha-galactosylceramide (α-GalCer) and tested their effectiveness at providing long-term protection against influenza virus infection in mice. Multiple formulations were developed for encapsulating the virus and adjuvant separately, and in combination. The MPs exhibited sustained release of both the virus and the adjuvant lasting more than a month. Co-encapsulation significantly increased the encapsulation efficiency (EE) of the vaccine but reduced the release duration. On the other hand, co-encapsulation led to a reduction in EE for the α-GalCer and a change in release profile to a higher initial burst followed by a linear release compared to a low initial burst and slower linear release. The α-GalCer also had considerably longer release duration compared to the vaccine. Mice injected with particle formulations co-encapsulating kPR8 and α-GalCer were protected from a lethal influenza virus infection 30 weeks after vaccination. This study demonstrates that PLGA MP based vaccines are promising for providing effective vaccination and possibly for replacing multiple doses with a single injection.

Transport of topical anesthetics in vitamin E loaded silicone hydrogel contact lenses.

Transport of surface active anesthetic drugs through silicone hydrogel contact lenses containing nanosized vitamin E aggregates is explored for achieving extended anesthetics delivery. Commercial silicone hydrogel contact lenses release most ophthalmic drugs including local anesthetics for only a few hours, which is not adequate. Here we focus on creating dispersion of highly hydrophobic vitamin E aggregates in the lenses as barriers for drug diffusion for increasing the release durations. This approach has been shown previously to be successful in extending the release durations for some common hydrophilic ophthalmic drugs. The topical anesthetic drugs considered here (lidocaine, bupivacaine, and tetracaine) are hydrophilic at physiologic pH due to the charge, and so these cannot partition into the vitamin E barriers. However, these surface active drug molecules adsorb on the surface of the vitamin E barriers and diffuse along the surface, leading to only a small decrease in the effective diffusivity compared to non-surface-active hydrophilic drugs. The drug adsorption can be described by the Langmuir isotherm, and measurements of surface coverage of the drugs on the vitamin E provide an estimate of the available surface area of vitamin E, which can then be utilized to estimate the size of the aggregates. A diffusion controlled transport model that includes surface diffusion along the vitamin E aggregates and diffusion in the gel fit the transport data well. In conclusion, the vitamin E loaded silicone contact lens can provide continuous anesthetics release for about 1-7 days, depending on the method of drug loading in the lenses, and thus could be very useful for postoperative pain control after corneal surgery such as the photorefractive keratectomy (PRK) procedure for vision correction.

Interaction of ionic surfactants with cornea-mimicking anionic liposomes.

The interaction of surface-active molecules with lipid bilayers is ubiquitous both in biological systems and also in several technological applications. Here we explore the interaction of ionic surfactants with liposomes whose composition mimics the ocular epithelia. In this study, liposomes with a composition mimicking ocular epithelia are loaded with calcein dye above the self-quenching concentration. The liposomes are then exposed to surfactants, and the rate of dye leaked from the liposomes due to the interaction of surfactants is measured. Both cationic and anionic surfactants at various concentrations and ionic strengths are explored. Results show that the liposome bilayer permeability to the dye increases on exposure to the surfactants, leading to the release of the dye trapped in the core. However, the dye release stops after a finite time, suggesting a transient increase in permeability followed by healing. The leakage profiles exhibit two different timescales for the cationic surfactant but only one timescale for the anionic surfactant. The total dye leakage increases with surfactant concentration, and at a given concentration, the dye leakage is significantly higher for the cationic surfactants. The timescale for the healing decreases with increasing surfactant concentration, and increasing ionic strength increases the dye leakage for the anionic surfactant. These results show that the surfactant binding to the lipid bilayer increases the permeability while the bilayers heal likely because of the surfactant jump from the outer to the inner leaflet and/or rearrangement into tighter aggregates.

Interaction of cationic drugs with liposomes.

Interactions between cationic drugs and anionic liposomes were studied by measuring binding of drugs and the effect of binding on liposome permeability. The measurements were analyzed in the context of a continuum model based on electrostatic interactions and a Langmuir isotherm. Experiments and modeling indicate that, although electrostatic interactions are important, the fraction of drug sequestered in the double-layer is negligible. The majority of drug enters the bilayer with the charged regions interacting with the charged lipid head groups and the lipophilic regions associated with the bilayer. The partitioning of the drug can be described by a Langmuir isotherm with the electrostatic interactions increasing the sublayer concentration of the drug. The binding isotherms are similar for all tricyclic antidepressants (TCA). Bupivacaine (BUP) binds significantly less compared to TCA because its structure is such that the charged region has minimal interactions with the lipid heads once the BUP molecule partitions inside the bilayer. Conversely, the TCAs are linear with distinct hydrophilic and lipophilic regions, allowing the lipophilic regions to lie inside the bilayer and the hydrophilic regions to protrude out. This conformation maximizes the permeability of the bilayer, leading to an increased release of a hydrophilic fluorescent dye from liposomes.

Bupivacaine binding to pegylated liposomes.

BACKGROUND: Local anesthetic drugs, such as bupivacaine, can cause severe toxicity. Lipid emulsions have been proposed and used clinically for treating such cases. Liposomes may be an alternative for overdose treatment because of their unique structures and surface charges, which allows them to act as high affinity drug "sinks" and remove bupivacaine from solution. METHODS: We conducted in vitro experiments with unilamellar and multilamellar anionic, polymer-coated liposomes to determine the amount of bupivacaine bound to liposomes in buffer solutions as a means of assessing the liposome-drug affinity. Binding experiments were also done in human serum to determine the liposomes' ability to compete with serum proteins for binding drug molecules. RESULTS: Unilamellar liposomes sequestered 60%-65% and 77%-85% of bupivacaine from buffer at 1.45 and 2.9 mg lipid/mL, respectively. The increased lipid loading increased the drug uptake at all drug concentrations measured (P = 0.001, 0.002, <0.001, and 0.003 for 5, 20, 35, and 50 microM, respectively). Multilamellar liposomes bound more drug per unit mass, with 71%-90% of the total bupivacaine bound at a phospholipid concentration of 1.45 mg lipid/mL. When comparing unilamellar and multilamellar liposomes at 1.45 mg lipid/mL, the multilamellar liposomes were significantly better at 3 of the 4 drug concentrations measured (P = 0.002, 0.001, 0.001, and 0.08 for 5, 20, 35, and 50 microM, respectively). In human serum samples, unilamellar liposomes (2.9 mg lipid/mL) reduced the unbound (free) drug by 36% (P = 0.037), 56% (P = 0.022), 47% (P = 0.042), and 50% (P = 0.018) for bupivacaine concentrations of 5, 20, 35, and 50 microM, respectively. CONCLUSIONS: The anionic, pegylated liposomes exhibit high binding for bupivacaine, both in buffer and in human serum. These results suggest that an IV injection of liposomes could be useful for the treatment of bupivacaine toxicity through drug redistribution.

Extended release of dexamethasone from oleogel based rods.

HYPOTHESIS: Topical and systemic methods are not able to deliver ophthalmic drugs for treatment of retinal diseases. Consequently, invasive monthly intravitreal injections through the eyeball are required to deliver retinal drugs. A reduction in the frequency of the injection through extended release of the drugs could have significant clinical benefits. EXPERIMENTS: Oleogels containing ethyl cellulose as the gelator at 10% (wt%) in soybean oil were loaded with dexamethasone above the solubility limit and expunged from a syringe to create cylindrical rods for extended drug delivery. The devices were imaged to explore particle distribution and drug release was measured under sink conditions in buffer. A model was developed and fitted to data to determine effective drug diffusivity. FINDINGS: Dexamethasone is released slowly due to the presence of the drug particles that serve as drug depots. The release increases from 600 to 3000 h as the drug loading is increased from 3% to 28%. The release profiles can be modeled by considering drug dissolution and diffusion, as well as the tortuosity of the matrix due to the presence of the voids formed after the drug particles have dissolved. The proposed approach is promising as the release profiles of the drug are comparable to commercial devices.

Pigmented contact lenses for managing ocular disorders.

Blocking a selected wavelength range from the light spectrum can have multiple benefits. Ultra-violet (UV) radiation is detrimental to the retina, necessitating its blocking through sunglasses and contact lenses. The near-visible light also has enough energy to cause damage but, is typically not blocked by commercial lenses. Filtering light can also be useful to patients with migraines, amblyopia, and color blindness. Here, to achieve blocking, incorporation of pigments extracted from colored agro-products into contact lenses is explored. Pigment extraction from food powders including turmeric, spinach, paprika, and woad powders in ethanol is demonstrated. Lens immersion in pigment concentrated ethanol is done to facilitate swelling, allowing rapid pigment uptake. Pigment incorporation ensures the absence of visible light scattering, lens opacity, and leaching. The characterization of pigmented lenses is done through absorptivity and transmittance measurements. Degradation measurements investigate the stability of the green pigment extract from spinach powder with time. p-HEMA and silicone hydrogels loaded with >400 µg/g turmeric pigment act as class 1 UV blockers retaining >90% visible light transparency and screening >95% of the UVR spectra. Spinach, paprika, and woad powder loaded silicone lenses mitigate >20% visible light transmission from selective wavelengths finding applications in photophobia, amblyopia treatment, and color vision deficiency management.

Evaluating the potential of drug eluting contact lenses for treatment of bacterial keratitis using an ex vivo corneal model.

Corneal infections are treated by multiple instillations of eye drops each day. This study aims to investigate the effectiveness of ofloxacin-loaded contact lenses as prolonged release devices for the treatment of bacterial keratitis. Two silicone hydrogel contact lenses (SHCLs) Senofilcon A (ACUVUE OASYS®) and Narafilcon A (ACUVUE TRUEYE®) were modified by incorporation of ofloxacin alone or with vitamin E (VE). The drug uptake and in vitro release kinetics were investigated and the antibacterial efficacy was assessed against Staphylococcus aureus and Pseudomonas aeruginosa in an ex vivo rabbit corneal model. The in vitro studies showed a higher uptake (p ≤ 0.05) and longer duration of release by Narafilcon A lenses compared to the Senofilcon A lenses. The addition of VE led to a significant increase in duration of release (p < 0.05) for both lenses. The ex vivo studies confirmed the effectiveness of the ofloxacin-loaded lenses in the reduction of bacterial load to clinically insignificant levels and ofloxacin-vitamin E-loaded Narafilcon A lenses in the reduction of bacteria on the corneas to undetectable levels. Antibiotic-loaded lenses are effective in the treatment of ocular infections. Incorporation of vitamin E will sustain this effect and eliminate the need for multiple instillations of eye drops.

Optimization of intraocular lens hydrogels for dual drug release: Experimentation and modelling.

Topical administration of both antibiotic and non-steroidal anti-inflammatory drugs after cataract removal surgery is usually recommended to avoid infection and inflammatory process development. In this work, a HEMA/MMA based hydrogel was developed as a platform for simultaneous release of an antibiotic (moxifloxacin) and a non-steroidal anti-inflammatory drug (diclofenac). Initially, hydrogels with different HEMA/MMA compositions and cross-linking contents were produced and loaded separately with moxifloxacin and diclofenac. The in vitro release profiles of the drugs from the hydrogels were obtained and a mathematical model was employed to estimate the concentration in vivo induced by such systems. The most promising hydrogel was then sequentially loaded with diclofenac and moxifloxacin, and the same mathematical model was applied to the in vitro release results. The results suggest that the dual-drug loaded hydrogel could potentially release effective amounts of antibiotic and anti-inflammatory for three weeks. Nonetheless, adjustment of the concentration profiles can be achieved for example by tailoring of the loading conditions.

Extended delivery of ophthalmic drugs by silicone hydrogel contact lenses.

We developed extended wear silicone hydrogel soft contact lenses that deliver ophthalmic drugs for an extended period of time ranging from weeks to months. Silicone hydrogels comprising of N,N-dimethylacrylamide, 3-methacryloxypropyltris(trimethylsiloxy)silane, bis-alpha,omega-(methacryloxypropyl) polydimethylsiloxane, 1-vinyl-2-pyrrolidone, and ethylene glycol dimethacrylate were prepared with varying ratios of monomers and transport of three different ophthalmic drugs, timolol, dexamethasone, and dexamethasone 21-acetate was explored. All the silicone hydrogels of 0.1 mm thickness exhibit diffusion limited transport and extended release varying 20 days up to more than three months depending on the compositions of hydrophobic and hydrophilic components of silicone hydrogels. Also, there are multiple time scales in transport of at least certain molecules, which is perhaps due to the complex microstructure of these gels. The mechanical and physical properties of lenses such as ion permeability, equilibrium water content, transparency, and surface contact angles of some of the gels are suitable for contact lens application.

Dexamethasone transport and ocular delivery from poly(hydroxyethyl methacrylate) gels.

We explore ocular delivery of dexamethasone (DX) via poly(hydroxyethyl methacrylate) (PHEMA) contact lenses, which are known to have a much higher bioavailability in comparison to eye drops. Three derivatives of dexamethasone (dexamethasone 21-disodium phosphate (DXP), dexamethasone, and dexamethasone 21-acetate (DXA)) are explored. These drugs are loaded in the gels by soaking in aqueous or ethanol solutions, and also by direct addition of the drug to the polymerizing mixture. Dynamic drug concentrations in the aqueous phase are monitored both in loading and release experiments. The data is utilized to determine the partition coefficients and the mean diffusivity, which includes contributions from both bulk and surface diffusion. Finally we utilize the transport model to predict the bioavailability of the three forms of dexamethasone for drug delivery via contact lenses. The transport of each of the drug is diffusion limited with diffusivities of 1.08 x 10(-11) and 1.16 x 10(-11) m(2)/s for DX and DXA, respectively. The diffusivities of DXP depend on concentration and on ionic strength, and are much smaller than those for DX and DXP. The bioavailability for delivery of these drugs via contact lenses is much higher than that for drops, and the bioavailability is the highest for DXA.

Ophthalmic delivery of Cyclosporine A from Brij-97 microemulsion and surfactant-laden p-HEMA hydrogels.

Cyclosporine A (CyA) is an immunosuppressant drug that is used for treating a variety of ocular diseases and disorders. CyA is commonly delivered via eye drops, which is highly inefficient due to a low bioavailability of less than 5%. The bioavailability of ophthalmic drugs can be substantially improved to about 50% by delivering them via contact lenses. This paper focuses on the development of nanostructured poly (2-hydroxyethyl methacrylate) (p-HEMA) hydrogels containing microemulsions or micelles of Brij 97 (C(18)H(35)(OCH(2)CH(2))(10)) for extended delivery of CyA. Release of CyA from these nanostructured hydrogels was performed in vitro to explore the mechanisms of release and the effects of surfactant concentration, processing conditions and storage on the release kinetics. Results show that the surfactant and microemulsion-laden gels can deliver CyA at therapeutic dosages for a period of about 20 days. Release of the drug is diffusion controlled with effective diffusivities decreasing with increasing surfactant loading. The release kinetics are relatively similar for both surfactant and microemulsion-laden gels with comparable surfactant loading. The results also show that these hydrogels retain their effectiveness even after exposure to all the relevant processing conditions including unreacted monomer extraction, autoclaving and packaging, and so these materials seem to be very promising for ophthalmic delivery of CyA and perhaps other drugs.

Drug and surfactant transport in Cyclosporine A and Brij 98 laden p-HEMA hydrogels.

Surfactants are commonly incorporated into hydrogels to increase solute loading and attenuate the release rates. In this paper we focus on understanding and modeling the mechanisms of both surfactant and drug transport in hydrogels. Specifically, we focus on Brij 98 as the surfactant, Cyclosporine A (CyA) as the hydrophobic drug, and poly-hydroxy ethyl methacrylate (p-HEMA) as the polymer. The models developed here are validated by experiments conducted with gels of different thicknesses and surfactant loadings. Also the model is compared with prior experimental studies in literature. The model predicts that the percentage surfactant as well as drug release scales as 1/(surfactant loading)(0.5), and thus a four fold increase in surfactant loading leads to a two fold reduction in percentage release for both drug and surfactant at a given time. The models for the surfactant and drug release are fitted to the experimental data to obtain values of 1.44 x 10(-14) m(2)/s for CyA diffusivity and 414.4 for the partition coefficient between drug concentration inside the micelle and that in the gel. These models can be very helpful in tuning the drug release rates from hydrogels by controlling the surfactant concentration. The results also show that Brij 98 loaded p-HEMA exhibit an extended release of CyA and so contact lenses made with this material can be used for extended ocular delivery of CyA, which is an immunosuppressant drug commonly used for treatment of various ocular ailments.

Uptake of amitriptyline and nortriptyline with liposomes, proteins, and serum: implications for drug detoxification.

Liposomes composed of DOPG and DMPC were studied for their ability to sequester amitriptyline and nortriptyline under physiological conditions. The liposomes reduced the free drug concentration in protein mixtures and in human serum, but the drug uptake efficiency of liposomes was reduced in the presence of plasma proteins, perhaps due to adsorption of proteins on the liposomes. The reduction was significantly more for the pure DOPG liposomes. The 50:50 DMPC:DOPG liposomes (0.72 mg lipid/mL) reduced the free amitriptyline concentration by 50-60% in the presence of 7% proteins (4% albumin (w/w), 2% fibrinogen (w/w), 1% globulins (w/w)). In human serum, the free drug reduction was 35-70% with the same 50:50 liposomes (0.72 mg lipid/mL). The liposomal systems were equally efficient at sequestering nortriptyline, which is a major metabolite of amitriptyline. The drug binding to liposomes in the presence of serum proteins is also quick and reversible and the likely mechanism of drug sequestration is adsorption of drug on the surface of liposomes. Accordingly, the drug uptake increases with increased charge and lipid loading. Even though the serum proteins reduced the effectiveness of the liposomes at sequestering the drug, the 50:50 DMPC:DOPG liposomes may be effective at treating amitriptyline overdose patients.

Timolol transport from microemulsions trapped in HEMA gels.

Approximately 90% of all ophthalmic drug formulations are now applied as eye-drops. While eye-drops are convenient and well accepted by patients, about 95% of the drug contained in the drops is lost due to absorption through the conjunctiva or through the tear drainage. A major fraction of the drug eventually enters the blood stream and may cause side effects [J.C. Lang, Adv. Drug Delivery Rev. 16 (1995) 39-43; C. Bourlais, L. Acar, H. Zia, P.A. Sado, T. Needham, R. Leverge, Prog. Retinal Eye Res. 17 (1998) 33-58; M.P. Segal, FDA Consumer Mag. (1991)]. The drug loss and the side effects can be minimized by using microemulsion-laden soft contact lenses for ophthalmic drug delivery [D. Gulsen, A. Chauhan, Invest. Ophthalmol. Vis. Sci. 45 (2004) 2342-2347; D. Gulsen, A. Chauhan, Abstr. Pap. Am. Chem. Soc. 227 (2004) U875]. In order for microemulsion-laden gels to be effective, these should load sufficient quantities of drug and should release it a controlled manner. The presence of a tightly packed surfactant at the oil-water interface of microemulsions may provide barrier to drug transport, and this could be used to control the drug delivery rates. In this paper we focus on trapping ethyl butyrate in water microemulsions stabilized by Pluronic F127 surfactant in 2-hydroxyethyl methacrylate (HEMA) gels and measuring the transport rates of timolol, which is a beta-blocker drug that is used for treating a variety of diseases including glaucoma. The results described here show that microemulsion-laden gels could have high drug loadings, particularly for drugs such as timolol base which can either be dissolved in the oil phase or form the oil phase of the microemulsions. However, the surfactant covered interface of the Pluronic microemulsions does not provide sufficient barrier to impede the transport of timolol, perhaps due to the small size of this drug.