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CONTENTS
Introduction Anatomy Factors affecting bioavailability Ocular diseases Drug delivery systems Case studies
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INTRODUCTION
77 FDA approved protein drugs 66/77 are recombinant proteins Protein pharmaceutical sales currently approach $25 billion/yr By 2012 they are expected to reach $60 billion/yr Peptides and proteins are expected to mitigate suffering in coming years as anticancer, hormones, analgesic antihypertensive, thrombolytics, growth factors, and many others.
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CHALLENGES
Complex and sensitive organ Ocular Tear Turnover Protease degradation Corneal Irritation Possibility Low Patient Acceptance
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ANATOMY
Anterior segment consists of front one-third of eye that mainly includes pupil, cornea, iris, ciliary body, aqueous humor, and lens . Diseases related to anterior segment are treated mainly through topical application of drugs.
The posterior segment consists of the back two-thirds of the eye that includes vitreous humor, retina, choroid, macula, and optic nerve . systemic dosing helps in the treatment of diseases affecting posterior segment of the eye.
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Clinically used drugs are generally small and fairly lipophilic. Thus, the corneal route is currently dominating. In both membranes, cornea and conjunctiva, principles of passive diffusion have been extensively investigated, but the role of active transporters is also being studied.
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PEPTIDE TRANSPORTER
These proton coupled transporters help in the translocation of di and tripeptides across the epithelium . These proteins are mainly classified into PepT1, PepT2 and peptide/histidine transporters (PHT 1 and PHT 2). Many drug molecules are known to be substrates for these transporters. Drugs including -lactam antibiotics, renin inhibitors and ACE inhibitors are known to be substrates for PepT1 and PepT2.
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Prodrugs (valine- ACVand valine-valine-ACV) exhibited higher concentrations of ACV in aqueous humor following systemic administration as compared to parent drug. This study indicates that peptide prodrugs are taken up via carrier mediated transport mechanism. Hence, drugs with poor ocular bioavailability can be suitably modified so that they can be recognized by peptide transporters.
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GLUCOSE TRANSPORTER
GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6 and GLUT7. GLU1, GLU3, and GLU4 are high-affinity glucose transporters GLUT5 is a high-affinity fructose transporter. GLUT2 is considered to be low affinity glucose transporter. GLUT7 is similar to GLUT2 but only expressed in endoplasmic reticulum . High substrate specificity of glucose transporters renders them inefficient for drug delivery purpose.
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VITAMIN C TRANSPORTER
AA levels in aqueous humor are partly responsible for preventing cataract. Two specific transporters (SVCT-1 and SVCT-2) of vitamin C were identified in the ocular tissues of human, rabbit and rat. Transport of AA across the cells is mediated by two different transporter families. One consists of the low affinity and high capacity facilitative hexose transporters (GLUT) which translocate dehydro ascorbic acid (oxidized form of ascorbic acid), and the other consists of high affinity and low capacity sodium dependent vitamin C transporters (SVCT1 and SVCT2) that ferries L-ascorbic acid (reduced form of ascorbic acid)
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EFFLUX TRANSPORTERS ABC transporters are broadly classified into two types (a) complete transporter, contains four units (two nucleotide-binding domains and two membrane bound domains) and (b) half transporter, which possesses only two units (one nucleotide-binding domain and one membrane-bound domain). Half transporter must attach with another half transporter to perform its action. These ABC proteins are actively involved in detoxification process by regulating the transport of various sterols, lipids, endogenous metabolic products and xenobiotics .
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Literature search reveals that mainly two multidrug efflux pumps are responsible for the development of chemoresistance (a) P-glycoprotein (ABCB1) and (b) multidrug resistant protein (MRP)(ABCC1). The presence of P-gp in the eye has been confirmed on conjunctival epithelial cells , ciliary non-pigmented epithelium , human and rabbit cornea , retinal capillary endothelial cells, iris and ciliary muscle cells.
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Zhang et al concluded that both BCRP and MRP2 have very low expression levels in the human cornea while there were moderate MRP1 expression levels in the human cornea. Moreover, designing drugs that can efficiently evade MRP1 efflux may play an important role in enhancement of ocular penetration
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BLOOD-OCULAR BARRIERS
The eye is protected from the xenobiotics in the blood stream by blood-ocular barriers. These barriers have two parts: blood-aqueous barrier and bloodretina barrier. The anterior blood-eye barrier is composed of the endothelial cells in the uvea. This barrier prevents the access of plasma albumin into the aqueous humor, and limits also the access of hydrophilic drugs from plasma into the aqueous humor. Inflammation may disrupt the integrity of this barrier causing the unlimited drug distribution to the anterior chamber. In fact, the permeability of this barrier is poorly characterised. The posterior barrier between blood stream and eye is comprised of retinal pigment epithelium (RPE) and the tight walls of retinal capillaries
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Unlike retinal capillaries the vasculature of the choroid has extensive blood flow and leaky walls. Drugs easily gain access to the choroidal extravascular space, but thereafter distribution into the retina is limited by the RPE and retinal endothelia. Despite its high blood flow the choroidal blood flow constitutes only a minor fraction of the entire blood flow in the body. Therefore, without specific targeting systems only a minute fraction of the intravenous or oral drug dose gains access to the retina and choroid.
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DISEASES
Glaucoma. Age-related macular degeneration (AMD) Diabetic macular edema (DME). Conjunctivitis. Dry eye syndrome. Keratitis. Iritis (anterior uveitis). Rosacea. Blepharitis (inflammation of the lid margins). Chalazia (Meibomian cysts of the eyelid). Corneal ulcer. Cataract. Croliferative vitreoretinopathy (PVR). Cytomegalovirus (CMV).
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DIABETIC RETINOPATHY
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DRUG DELIVERY
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DRUG DELIVERY
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NDDS
PRO-DRUG FORMULATIONS AND PERMEABILITY ENHANCERS Use of more lipophilic inactive derivatives advantages in various properties like solubility, stability, permeability and evasion of efflux pump have been gained. OCULAR ENZYMES Proteases, esterases, ketone reductase, and steroid 6 hydroxylase. DRUGS Ganciclovir (also as intravitreally by injection or as a nonbiodegradable reservoir system). Acyclovir. 5-flurocytosine, a prodrug of 5-fluorouracil, administered after subconjunctival transplantation of cells containing the converting enzyme cytosine deaminase.
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DRUGS Quinidine- efflux TG100801- toxicity UNIL088 Cannabinoids Combretastatin A-4-phosphate Nepafenac
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PERMEATION ENHANCERS
Increased corneal penetration into the anterior segments can be achieved with the addition of permeability enhancers to the drug formulation (Davis et al., 2004). EXAMPLES Surfactants, bile acids, chelating agents have all been used. Cyclodextrins, cylindrical oligonucleotides with a hydrophilic outer surface and a lipophilic inner surface that form complexes with lipophilic drugs, are among the more popular permeability enhancers. They have been used with corticosteroids, choloramphenicol, diclofenac, cyclosporine, and sulfonamides, carbonic anhydrase inhibitors.
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CYCLODEXTRINS Dexamethasone Zinc diethyldithiocarbamate Disulfiram Inclusion complexes were prepared with rhEGF/HP- -CD which were suspended in poloxamer gel.
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INJECTABLE THERAPIES
INTRA-VITREAL INJECTION Injection of drug solution directly into vitreous using a 30 G needle. Offers higher drug concentrations in vitreous and retina. Elimination of drugs following intravitreal administration depends on their molecular weight. Linear and globular shaped molecules (especially protein and peptide drugs) with molecular weight greater than 40 and 70 kDa respectively tend to cause longer retention in vitreous humor.
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DISADVANTAGES: Retinal detachment, endophthalmitis and intravitreal hemorrhages. Patients need to be carefully monitored following intravitreal injections. DRUGS Fomivirsen (Vitravene), which delays cytomegalovirus retinitis in patients with AIDS, was the first biologic approved for intravitreal injection. (VEGF)specific inhibitors that bind VEGF-A, such as the aptamer pegaptanib (Macugen; Ng and Adamis, 2006) and the antibody fragment ranibizumab (Lucentis; Ferrara et al., 2006),
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Bevacizumab (Avastin), a whole humanized mouse antibody that binds to VEGF and was developed for intravenous treatment for metastatic colorectal cancer, is currently being used intra-vitreally off-label for treatment of AMD, although the intraocular safety profile remains unknown (Morris et al., 2007). Intravitreal administration of triamcinolone acetonide for the treatment of diabetic retinopathy, uveitis, pseudophakic cystoid, macular edema, choroidal neovascularization associated with AMD, and macular edema associated with central retinal vein occlusion (Davis et al., 2004).
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PERIOCULAR ROUTES
Includes subconjunctival, retrobulbar, peribulbar, and, posterior juxtascleral (Ghate and Edelhauser, 2006). SUBCONJUCTIVAL ROUTE attempt to minimize dosing frequency maintains a sustained drug delivery to the anterior and posterior segment during a prolonged period of time. Hydrophilic drugs, which penetrate through the sclera, are more effective when given by the subconjunctival route, because they do not have to penetrate the conjunctival epithelium.
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POSTERIOR JUXTASCLERAL The angiostatic steroid anecortave (Retaane) is injected as a depot formulation via a specialized cannula in a posterior juxtascleral position (sub-Tenons space) and is being investigated as a treatment for AMD (Davis et al., 2004). One problem with this route of administration is reflux of the drug from Tenon space, so further work is currently being carried out to address this problem (Morris et al., 2007).
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Ghate et al., studied the pharmacokinetics of sodium fluorescein following periocular administration in rabbits. The study concluded that administration of drug via subtenon injection resulted in the highest and sustained vitreous concentration of sodium fluorescein compared to retrobulbar and subconjunctival routes . Anterior segment complications have been observed in some patients following periocular injections. They include rise in intraocular pressure, cataract, hyphema, strabismus and corneal decompensation.
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Drugs including nucleic acids such as antisense oligonucleotides, aptamers, and small interfering RNAs, are being investigated with nanosphere and microsphere ocular drug delivery methods to enhance their cellular penetration, protect against degradation, and allow long-term delivery EXAMPLES- Piloplex .
Nanosized complexes of antisense TGF-2 phosphorothioate oligonucleotides (PS-ODN) with polyethylnimine (PEI) and naked POS-ODN were encapsulated into poly (lactide-co- glycolide) microsphere.
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Gaini et al. formulated poly (lactide-co-glycolide) microsphere as a carrier for the topical ocular delivery of peptide drug vancomycin with high and prolonged vancomycin concentration and increased AUC values (Two fold) with respect to an aqueous solution of the drug. The formulation developed of rhVEFG in poly (D, Llactideco-glycolide) (PLG) microsphere that provide a continuous local delivery of intact protein. Sorin et al. developed a new ophthalmic delivery system, pilocarpine loaded proteinaceous (gelatin albumin) microspheres for better ocular bioavailability.
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NANOSUSPENSIONS Cloricromene (AD6) was formulated in nanosuspensions by using eudragit RS100 and RL100. AD6-loaded eudragit nanoparticle suspension offered a significant edge in enhancing the shelf life and bioavailability of the drug following ophthalmic application.
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MICROEMULSIONS
Indomethacin, chloramphenicol An oil-in- water system consisting of pilocarpine using lecithin, propylene glycol, PEG 200 as surfactant/co surfactants, and isopropyl myristate as the oil phase has been designed, which is nonirritating to the rabbit animal model. Timolol in microemulsion system was laden in a 2hydroxyethyl methacrylate (HEMA) gels which was studied to modulate its transport across the gel. Sirolimus, a highly lipophilic drug with aqueous solubility of 2.6 g/mL was formulated in microemulsion system which could hold 1 mg of drug in the system with excellent stability and tolerability.
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LIPOSOMES
Liposomes, a type of nanoparticle or microparticle, are vesicular lipid systems of a diameter ranging between 50 nm and a few micrometers. They allow encapsulation of a wide variety of drug molecules such as proteins, nucleotides, and even plasmids and can be injected under a liquid dosage form (27- to 30-gauge needle). They provide a convenient way of obtaining slow drug release from a relatively inert depot.
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Another advantage of liposomes is that encapsulated drugs appear to be less toxic, because only a limited amount of drug comes in direct contact with ocular tissues. Similar to microparticles and nanoparticles, however, liposomes can also impair vitreous clarity. Furthermore, the long-term effects of liposomal injections in the eye are unknown (Hsu, 2007).
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NIOSOMES
Cyclopentolate, niosomal formulation released the drug independent of pH resulting in significant enhancement of ocular bioavailability. Niosomal formulation of coated (chitosan or carbopol) timolol maleate exhibited significant IOP lowering effect in rabbits as compared to timolol solution.
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DISCOMES
Large structures with a size range of 1216 m derived by incorporating nonionic surfactant Solulan C24 in niosomes. A major advantage of this system was less systemic drainage because of the large size and large residence time in the cul-de-sac due to their disc shape. Timolol maleate was successfully entrapped in discomes and niosomes. In vivo bioavailability of the discomes was better than the niosomes
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DENDRIMERS
Synthetic, spherical, macromolecules named after their characteristic tree like or dendritic branching around a central core, which possess unique properties (multivalency, globular architecture and well defined molecular weight) that makes them a new scaffolds for drug delivery, especially if formulated as micelles may prove effective vehicles for ocular drug delivery .
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Vandamme developed poly (amidoamine) (PAMAM) dendrimers for controlled ocular drug delivery of pilocarpine and tropicamide . Devarakonda designed Polyamidoamine (PAMAM) Dendrimers for Water-Insoluble Nifedipine . Marano et al have have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) into the eyes of rats and inhibit laser-induced choroidal neovascularization (CNV) .
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OCULAR IMPLANTS
Advantages Delivering constant therapeutic levels of drug directly to the site of action. Release rates are typically well below toxic levels, and higher concentrations of the drug are therefore achieved without systemic side effects. Subconjunctival implantation is used for anteriorsegment diseases, whereas intravitreal and suprachoroidal methods are typically used to treat posterior-segment diseases. Intrascleral implants can be used for either.
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Biodegradable implants have the advantage of being able to be fashioned into many shapes, they are amenable for injection as an office procedure, they do not require removal, and they increase the half-life of the drug (Hsu, 2007).
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IONTOPHORESIS
Electric current is applied to enhance drug penetration into tissue. The drug is applied with an electrode carrying the same charge as the drug, and the ground electrode, which is of the opposite charge, is placed elsewhere on the body to complete the circuit. The drug serves as the conductor of the current through the tissue.
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Transcorneal and transcleral iontophoresis have been studied with a variety of ophthalmic drugs including oligonucleotides, in animals, and more limited data are available for humans. Iontophoresis has the advantage of being noninvasive, and therefore, it avoids the risks of surgical implantation or intravitreal injections but does not increase drug halflife. Animal studies have shown that transcleral iontophoresis can be used to deliver therapeutic levels of bioactive proteins to the retina and the choroid, which may be a viable and less invasive alternative for delivering antiPowerpoint Templates Page 62
OcuPhor/pegaptanib commercially available iontophoresis unit. It consists of drug application dispersive electrode and an electronic iontophoresis dose controller. A hydrogel pad to absorb the drug formulation and a small flexible wire to connect the conductive element to the dose controller. The drug pad is hydrated with drug solution immediately prior to use and the applicator is placed on the sclera of the eye under the lower eye lid. Preliminary clinical studies in human volunteers have shown that the OcuPhor system is well tolerated over a wide range of both positive and negative polarity current and does not produce any ophthalmic changes.
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Iomed used a model anionic drug, diclofenac to investigate the interstudy and intrastudy reproducibility of transscleral iontophoresis to rabbit eyes. Significant amount of diclofenac was found in retina / choroid tissues on average iontophoresis resulted in approximately a 16-fold increase of diclofenac concentration in retina choroid as compared to passive no current control. Relatively small amount of drug were delivered systemically, indicating predominantly local delivery to the eye, with the transscleral Iontophoresis.
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EYEGATE II:
Safely enhances drug penetration and reduces dosing frequency Simple in-office procedure 1 to 4 minutes Multiple clinical studies completed Over 300 patients and 900 treatments performed Compatible with a variety of therapeutics Broad international patent protection on system and drug products
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The EGDS utilizes an inert electrode, which electrolyzes water to produce the hydroxide or hydronium ions required to propel charged drug molecules. In both strategies, the drug product solution contains ample buffering capacity to accommodate the generation of hydroxide or hydronium ions.
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In situ gels are promising ocular drug delivery systems since they are conveniently dropped into the eye as a liquid where after they undergo a transition into a gel as a result of special physical / chemical changes (for example pH, temperature, and a specific ion) in their environment; in this case a cul-de-sac . Due to their elastic properties hydrogels resist ocular drainage leading to longer contact times. Hydrogel is the most common method of improving the ocular availability of drugs to increase precorneal residence time.
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Qi et al. developed a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system containing poloxamer analogs and carbopol. The incorporation of carbopol 1342P NF not only did not affect the pseudoplastic behavior but also enhanced the mucoadhesive force significantly and sustained the drug release over a period of 8 h . Kamel et al. developed a pluronic F 127 based formulations of timolol maleate (TM) aimed at enhancing its ocular bioavailability. In vivo study showed that the ocular bioavailability of TM, measured in albino rabbits, increased by 2.5 and 2.4 fold for PF127 gel formulation compared with 0.5% TM aqueous solution .
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The mixture of 0.3% carbopol and 14% pluronic solutions showed a significant enhancement in gel strength in the physiological condition. The pilocarpine release was extended upto 6h by using this system . Miyazaki et al. were developed a thermoreversible gel formed in situ by aqueous solution of an enzyme degraded xyloglucan polysaccharide for sustained release vehicle for the ocular delivery of pilocarpine hydrochloride. Grafting of poloxamer onto the hyaluronic acid for in situ gelling ophthalmic drug delivery system for ciprofloxacin was reported by Cho et al . Yanxia et al. investigated a novel thermosensitive copolymer (poly 9 N- isopropylacrylamide) chitosan (PNIPAAm- Cs) for its thermosensitive in situ gel forming properties and potential utilization for ocular drug delivery for timolol maleate over a period of 12 h .
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Pandit et al developed the in situ gelling system for Indomethacin by using ion sensitive sodium alginate. The release of indomethacin was extended upto 8 h. Mourice and Srinivas found a two fold increase in the permeation of fluoroscein in humans by using gellan gum compared to an isotonic buffer solution [25]. Pan et al. developed ophthalmic system of gatifloxacin using alginate (Kelton) in combination with HPMC (methocel E50LV) which acted as a viscosity enhancing agents. In vivo precorneal retention studies indicated that the alginate / HPMC solution retained the drug better than the alginate or HPMC alone [26].
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The pH triggered in situ gel of antibacterial agent; ofloxacin for ophthalmic delivery was developed by Srividya et al. Polyacrylic acid (Carbopol 940) [27]. Polycarbophil based pH triggered in situ gelling system was reported. Polycarbophil is insoluble in water, but its high swelling capacity in a neutral medium permits the entanglement of the polymer chains with the mucus layer [28]. Lindell and Engstrom reported an in situ thermogelling system consisting of ethyl (hydroxyethyl) cellulose and a charged surfactant releasing slowly timolol maleate [29].
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Pluronic F-127-g-poly (acrylic acid) copolymer based in situ gelling vehicle was found to have prolonged precorneal residence time and improved ocular bioavailability. The studies indicated that the drug release rates decreased as acrylic acid / pluronic molar ratio and copolymer solution concentration increased . Sol-to-gel system of ciprofloxacin hydrochloride was prepared by utilizing the phase transition properties of hydroxyl propylmethyl cellulose K15M and carbopol 934. Lui et al developed Aginate / HPMC based system for long acting delivery of gatifloxacin [32].
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MICRO NEEDLE
An evaluation of coated solid metal microneedle to deliver the drug was carried out both in-vitro and in-vivo. Microneedle had shown excellent in vitro penetration into sclera and rapid dissolution of coating solution after insertion. In-vivo drug level was found to be significantly higher than the level observed following topical drug administration. This mode of drug delivery was also successful in the delivery of pilocarpine . The inventors haveclaimed to deliver drug successfully across both sclera and cornea by coated microneedle with minimum invasion.
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GENE DELIVERY
Vitravene, an ODNs for the treatment of CMV in AIDS patients and Macugen (pegaptanib sodium injection) which is an aptamer for the treatment of wet AMD.
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Eye-Instill produced by Med-Instill Inc., which have one way valve to ensure multiple dosings of sterile, preservative free drug solution. The OptiMyst device, which dispenses medication as a mist rather than as a drop. The latter provides much less medication per dose, below blink and lachrymation thresholds.
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UNDER DEVELOPMENT
VersiDoser TM drug delivery system under development by Mystic pharmacueticals, Inc., holds the near term potential for setting new slandard for effective FOTE drug delivery. The VersiDoser platform utilizes the pack with Novel multidose delivery device that dispenses the drug into the eye in a predictable manner irrespective of the orientation of the device and the eye. These devices are capable of the self administered precision dosing in the 12-15 l range and provide automatic dose counters. Design significantly enhanceS compliance, ease of use and therapeutic benefits for elderly and padiatric patients. Powerpoint Templates
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An electrochemical intraocular drug delivery device, Sensors and Actuators A 143 (2008) 4148 The advantages of MEMS fabrication for producing miniaturized and efficient drug delivery systems have already been realized for insulin delivery and delivery of bioactive compounds to neural tissue This device contained a drug reservoir attached to a flexible checkvalved cannula that was directed through the eye wall by means of a small surgical incision. This configuration allowed drug to be delivered directly into the eye and reach intraocular tissues in the vicinity of the cannula outlet. To deliver drug into the eye, the device was actuated by manually depressing the drug reservoir. This action generated an overpressure in the reservoir which in turn caused a check valve in the cannula to open and allow drug to enter the intraocular space. The reservoir was emptied over time by repeated dosing by manual actuation. Upon depletion of the reservoir, the drug reservoir was refilled by puncturing the reservoir wall with a syringe needle and emptying the syringe into the reservoir.
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CASE STUDY
EFFECT OF BENZALKONIUM CHLORIDE ON TRANSSCLERAL DRUG DELIVERY INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, FEBRUARY 2005, VOL. 46, NO. 2
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PURPOSE: To investigate the effect and safety of benzalkonium chloride on transscleral drug delivery in the rabbit after continuous intrascleral administration. TERMS BP : Betamethasone-21-phosphate BAK : Benzalkonium chloride. FD: Fluorescein isothiocyanate dextran
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RESULTS
BAK increased concentrations of BP in the vitreous and retina-choroid compared with the control. BP was not detected in the aqueous humor. In the in vitro study, BAK did not increase the scleral permeability of BP. In the retina-choroid, BAK significantly increased concentrations of FD-20 but did not increase those of FD-70. The addition of BAK did not increase concentrations of FD-20 or -70 in the vitreous. No substantial toxic reactions were observed in the retina in electrophysiological or histologic examinations after the addition of BAK.
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DATA
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Light micrographs of the retina after continuous intrascleral administration of 0.05% (A) and 0.5% (B) BAK aqueous solution. Powerpoint Templates
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Low- (A) and high- (B) magnification transmission electron micrographs of the retina after continuous intrascleral administration of 0.05% benzalkonium chloride (BAK) aqueous solution. (A) No abnormal change was observed; (B) tight junction (black arrowheads) and microvilli (white arrowheads) of the retinal pigment epithelium showed no abnormalities. Original magnification: (A) 2000; (B) 5000. Powerpoint Templates Page 91
CONCLUSIONS
The results of this study demonstrate that BAK may improve the ocular penetration of a drug in a transscleral drug delivery system without producing toxic reaction.
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REFERENCES
Safety evaluation of ocular drug delivery formulations: techniques and practical considerations TOXICOLOGIC PATHOLOGY, 36:49-62, 2008. Formulation approaches in ocular drug delivery system IJPT 2010 , 2 ,118-145. Drug delivery to eye: special reference to nanoparticles INTERNATIONAL JOURNAL OF DRUG DELIVERY 2 (2010) 12-21.
An electrochemical intraocular drug delivery device SENSORS AND ACTUATORS 143 (2008) 4148.
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Smart Polymers for Controlled Delivery of Proteins and Peptides: A REVIEW OF PATENTS RECENT PATENTS ON DRUG DELIVERY & FORMULATION 2009, 3, 4048. Glimpse on protein drug delivery: an utmost research area for biopharmaceuticals INT.J.DRUG DEV. & RES., APRIL-JUNE 2010, 2(2): 336-347 Systemic delivery of insulin via an enhancer-free ocular device JOURNAL OF PHARMACEUTICAL SCIENCES VOLUME 86, ISSUE 12, PAGES 13611364, DECEMBER 1997
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Challenges and obstacles of ocular pharmacokinetics and drug delivery, ADVANCED DRUG DELIVERY REVIEWS 58 (2006) 11311135 Ocular Iontophoresis for Drug Delivery, RETINA TODAY I MARCH 2011
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