Drug Delivery Systems

Commonly used ophthalmic drug formulations, such as solutions, gels, suspensions, and ointments, deliver drugs at rates that follow first-order kinetics, in which the concentration of the drug transferred to the eye decreases exponentially with time. To achieve a constant concentration of the drug in the precorneal tear film and create a steady-state concentration in the tissues, an ophthalmic drug delivery system needs to be designed to deliver a specific drug at a zero-order kinetic rate. At a zero-order kinetic rate of delivery, the rate is not proportional to the drug concentration but is related to some functional capacity involved in the transfer of drug.34 Solid ocular inserts have been designed to achieve this goal.

The release of drug from a solid insert may be controlled by the diffusion rate of the drug through the polymer container.50 Diffusion-controlled systems are either the reservoir type or the matrix type. In the matrix type of solid insert, the drug is dispersed throughout the polymer matrix and must diffuse through the matrix structure to be released. In contrast, a reservoir type of insert consists of a core of drug encapsulated within polymer layers that are not biodegradable and serve as a rate-controlling barrier to diffusion.34

1.6.1 Ocusert. Ocusert is a diffusion-controlled, reservoir-type device marketed in the United States that became commercially available in 1974. The device consists of a two-membrane sandwich of ethylene vinyl acetate with a pilocarpine reservoir in the center. A retaining ring of ethylene vinyl acetate impregnated with titanium dioxide for visibility and handling of the insert encloses the drug reservoir cir-cumferentially (figure 1.3).51 The pilocarpine is bound to alginic acid and is present as a free base, partly in an ionized form and partly in a nonionized form. The device is sterile and contains no preservative.52,53 The drug release from a reservoir type of diffusion-controlled system is provided by interaction between the polymeric membrane and the drug contained in the reservoir, and the surface area and thickness of the polymer layer.34,51 The ethylene vinyl acetate membrane is hydrophobic, which allows the nonionized form of pilocarpine to permeate but excludes water from the device.

The major factor in the rate of drug release is the driving force of the concentration gradient between the saturated concentration of drug within the reservoir

Ocusert Pilo System
Figure 1.3. Ocusert. (A) Construction of device. Annular ring surrounding reservoir is opaque white for visibility in handling and inserting system. (B) Device in position. Courtesy Akorn, Inc.

and the concentration of drug outside the membrane.34 Tear flow prevents the buildup of a stagnant layer of drug around the device and therefore maintains the concentration gradient across the membrane. As long as this gradient exists, the drug is released into the tear film at a constant rate over almost the entire lifetime of the device.54 However, during the initial 6-8 hours following insertion of the device, there is a higher pulsed release of pilocarpine because of the amount of drug previously equilibrated into the barrier membrane. The rate of release in this initial period can be as high as three or four times the desired rate.55,56

The device is marketed in two sizes, Ocusert Pilo-20 and Ocusert Pilo-40, representing two different in vitro release rates, 20 and 40 mg/h, respectively. The higher rate for Ocusert Pilo-40 is achieved by making its rate-controlling membranes thinner and by use of the flux enhancer di(2-ethylhexyl)phthalate.57 The devices are designed to release the drug for approximately 7 days.

Because of individual differences, direct comparisons between the Ocusert systems and various concentrations of pilocarpine drops cannot be made. A majority of patients controlled with pilocarpine 0.5% and 1% drops can usually be controlled with Ocusert Pilo-20. Most patients who required 2% or 4% solution of pilocarpine will require Ocusert Pilo-40.51,55

Pilocarpine Ocusert has several advantages over pilocarpine drops. It delivers pilocarpine at a very low constant rate over a 7-day period, except for the higher rate of release in the initial 6-8 hours. During the remainder of the 7-day period, the release rate is within ± 20% of the rated value. Satisfactory ocular hypotensive response is maintained around the clock for 7 days. A low baseline amount of miosis and induced myopia persists for the therapeutic life of the Ocusert system. The total amount of drug delivered to the eye is substantially less than with pilocarpine drop instillation.58 The risk of ocular or systemic pilocarpine toxicity is reduced. Studies have shown that Ocusert Pilo-20 produced less shallowing of the anterior chamber, miosis, accommodation myopia, and reduction in visual acuity than did pilocarpine 2% drops.59,60 It may provide better compliance because it is inserted only once a week. Because Ocusert offers continuous drug release, diurnal variations of IOP may be stabilized.

Despite these theoretical advantages, Ocusert has not achieved widespread popularity in clinical practice, because it requires detailed instruction and encouragement of patients to use it. Patients are instructed to place the insert in the inferior fornix, but in case of retention difficulty, it may be placed in the superior fornix. The insert may be lost from the eye without the patient noticing it; then the patient does not have the benefit of the drug. In practice, the major complaints with the insert are excessive foreign-body sensation and retention difficulty.61 Another disadvantage of the insert system is its relatively higher cost compared to pilocarpine drops. Furthermore, cases of sudden leakage of the drug have been reported.62 Ocusert is no longer commercially available.

1.6.2 Liposomes. Liposomes are microscopic vesicular structures consisting of lipid bilayers separated by water or an aqueous buffer compartment used to carry drugs (figure 1.4). They may consist of a single bilayer lipid membrane or a series of concentric multiple bilayer lipid compartments. They are classified as small unilamellar

Medical Images Compartment Pressure

Figure 1.4. Liposome bilayer membranes are formed when phospholipids arrange themselves such that hydrophilic heads are oriented toward aqueous phase and hydrophobic tails are oriented away from aqueous phase. Redrawn with permission from Price CI, Horton J. Local Liposome Drug Delivery: An Overlooked Application. Austin, Tex: RG Landes Co; 1992.

Figure 1.4. Liposome bilayer membranes are formed when phospholipids arrange themselves such that hydrophilic heads are oriented toward aqueous phase and hydrophobic tails are oriented away from aqueous phase. Redrawn with permission from Price CI, Horton J. Local Liposome Drug Delivery: An Overlooked Application. Austin, Tex: RG Landes Co; 1992.

vesicles if the size of the unilamellar vesicles is <100nm, or as large unilamellar vesicles if the size is >100nm.63 Multivesicular liposomes are another type of liposome, consisting of a cluster of numerous monolayered vesicles surrounded by an outer lipid monolayer. An aqueous droplet is entrapped within each vesicle.64

Hydrophilic drugs are encapsulated within the internal aqueous compartments, and lipophilic drugs are intercalated with the hydrophobic phospholipid bila-yer. The drugs are released by diffusion processes into the surrounding aqueous environment.65

Typical phospholipids used to form liposomes are phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidic acid, sphingomyelins, cardiolipin, plasmalogens, and cerebrosides. Steroid cholesterol and its derivatives are often included as components of liposomal membranes to improve the membrane stability. Liposomes can be prepared by sonication of dispersions of phospholipids, reverse-phase evaporation, solvent injection, detergent removal, or calcium-induced fusion.34

Liposomes have been widely investigated as delivery systems for a variety of ocular drugs because of their potential advantages. The major advantage ascribed to liposomal formulation is the ability to circumvent cell membrane permeability barriers by cell membrane-liposome interactions. Liposomes can potentially control the rate of release of the encapsulated drug, protect the drug from metabolic enzymes, reduce drug toxicity, enhance the therapeutic effects, and increase the possibility of ocular drug absorption by the close contact of the liposomes with corneal and con-junctival surfaces. Liposomes are biodegradable and nontoxic.65 Their drug delivery properties can be manipulated by incorporating and modifying the composition of the lipid bilayer.

The ocular availability to the target tissue of the drug entrapped within the liposomes is associated with the manner in which the drug interacts with the constituents of the vesicles, the interaction of the tissue cells with the liposomes, and the ocular residence time.

The rate of efflux of entrapped drugs from liposomes is governed by the physio-chemical characteristics of the drug, in addition to the properties of the liposome membrane. Most phospholipids exhibit a phase change from the gel crystalline state to the liquid crystalline state at a specific temperature, called the transition temperature. Varying the phospholipid by adjusting the combination of fatty acid chain length, degree of unsaturation, and polar head group structure can change the transition temperature. The phospholipid bilayer becomes more permeable to the entrapped materials at the liquid crystalline state above the transition temperature. The efflux rate can also be manipulated with incorporation of cholesterol into the bilayer. Decreasing acyl chain length and degree of unsaturation of the phospholipid may increase the permeability of the bilayer. The presence of charged phospholipid in the bilayer may affect the efflux by its interaction with the charged entrapped materials.65

Several mechanisms have been proposed for the interactions between the cells and the liposomes and have been reviewed in detail: (1) intermembrane transfer, (2) contact release, (3) adsorption, (4) fusion, and (5) endocytosis.65-67 The major mechanisms of interaction between liposomes and corneal epithelial cells are probably adsorption and intermembrane transfer.

1. Intermembrane transfer is the insertion of the lipophilic materials situated in the liposome membrane into other membranes. It occurs when the distance between the two membranes is small enough.

2. Contact release can occur when the membrane of the cell and the liposome experience perturbation as a result of contact. The entrapped aqueous solute molecules leak from the liposome into the cell.

3. Adsorption of the liposome to the cell surface takes place as a result of binding by specific receptors or specific cell-surface proteins. Adsorption brings the liposome into close contact with the cell surface.

4. Fusion occurs when the cell membrane and the liposome come into close contact. The bilayer can fuse together to release the contents of the liposome into the cytoplasm.

5. Endocytosis is considered to be the dominant interaction between liposomes and cells. The cell takes the liposome up into an endosome, which then fuses with a primary lysosome to form a secondary lysosome. Lysosomal enzymes break open the liposome and release the aqueous contents of the liposome. Liposomes may also be taken up by receptor-mediated endocytosis. However, the cornea has been demonstrated to exhibit poor phagocytic activity.

To serve as a topical ocular drug delivery system, liposomes must remain in the conjunctival cul-de-sac long enough to release their contents. Much research has concentrated on methods to increase the precorneal residence of liposomes. At physiologic pH, the corneal epithelium is negatively charged. Therefore, the positive surface charge of a liposome significantly increases the residence time of liposomes in the precorneal region. Retention also increases with smaller mean liposome size.68 However, there is a lack of specificity of the association of the liposomes for the cornea. The reduced drainage rate of liposomes was also attributed to their affinity for the conjunctival membranes. Specific binding to the cornea surface can be achieved by conjugating ligands on the corneal surface to the liposome. For instance, one approach is the incorporation into the liposomal membranes of a glycoprotein and the subsequent use of lectins to bind the glycoprotein to carbohydrate moieties associated with the target cells.69 The other possibility is to bind the liposome to the surface of the target tissue with the use of antibodies directed against the target tissue.65

Other investigative methods to prolong residence time have been studied. One of the methods is the formulation of a liposome with a positively charged vesicle-forming lipid component, usually an amine-derived phospholipid of a specific struc-ture.65 These vesicles have been shown to enhance precorneal retention. Viscosity-enhancing polymers such as hydroxypropyl methylcellulose or polyvinyl alcohol have been used to suspend the liposomes. Liposomes suspended in these polymer solutions were retained on the corneal surface for a significantly longer period. Attempts have also been made to coat phospholipid vesicles with a mucoadhesive polymer, poly(acrylic) acid, to enhance the precorneal retention of the vesicles.65

Liposomes may be administered subconjunctivally or intravitreally. Liposome-encapsulated antimicrobial agents improve the ocular delivery of antibiotics following subconjunctival administration. Subconjunctival injections of encapsulated gentamicin improved corneal concentration.70 The liposomal form provided higher drug concentrations in the sclera and cornea up to 24 hours after injection. Studies of liposome-bound cyclosporine injected subconjunctivally found this delivery system to achieve an aqueous concentration about 40% higher than injected free cyclosporine.71

Intravitreal injection of liposomes encapsulated with a variety of drugs has demonstrated therapeutic vitreal concentrations of those drugs. The drugs studied so far are gentamicin, amphotericin B, cyclosporine, and antiviral agents.70,72,73 Liposome-bound cyclosporine administered intravitreally resulted in a prolongation of the half-life of the drug to about 3 days.74 Several studies also reported a prolongation of vitreal levels of antiviral agents following intravitreous injection of the liposome-encapsulated form.65 Different methods are available to target liposomes either to promote the interaction between specific cells or tissues and the encapsulated drug or to release the contents of liposomes at specific sites. Liposomes containing acyclovir combined with a monoclonal antibody to herpes simplex virus glycoprotein D were studied to target the antiviral agent specifically to the infected cells.75,76 Another approach to targeting drug-bound liposomes to a specific site is the use of a heat-sensitive liposome. Triggering mechanisms such as an argon laser or microwaves to elevate the temperature at a specific site to release the contents of liposomes have been studied.65

Liposomes present a potential advantage in drug delivery. However, the routine use of liposome formulation as a topical ocular drug delivery is limited by their short shelf-life, their limited drug-loading capacity, and difficulty in stabilizing the preparation.65 Liposomes have been shown to achieve a prolonged therapeutic level when administered subconjunctivally and intravitreally. Much research is needed to further understand the various parameters that may influence liposomal ocular drug delivery.

1.6.3 Slow-Release Contact Lenses. Ocular bioavailability of conventional ophthalmic formulations is generally limited because of protective mechanisms, such as tear drainage and blinking, even with improved formulations such as viscosity enhancers or in situ gelling system. Medicated contact lenses that can be loaded with drug and release the drug on the ocular surface may be particularly useful for increasing drug bioavailability and may also correct impaired vision. The feasibility of this approach depends on whether the drug and contact lens material can be matched so that the lens absorbs a sufficient quantity of drug and releases it in a controlled fashion. In general, drug-loading capacity of conventional soft contact lenses is insufficient to be used for ophthalmic drug delivery. To overcome this drawback, the application of the molecular imprinting technology has been used in the design of soft contact lenses.77

Molecular imprinting refers to the synthesis of a polymer in the presence of the species to be absorbed in such a way that on removal of these template molecules, the polymer is left with a high concentration of cavities with special affinity for the desired absorbate.77 One of the applications of this technology in ocular drug delivery is timolol administration from hydrogels in soft contact lenses.78

Timolol maleate is a suitable molecule for the imprinting system because of its multiple sites of interaction with the functional monomer, and it is stable in solution at the temperatures used for polymerization of hydroxyethyl methacrylate (HEMA). Poly(hydroxyethyl methacrylate) (poly-HEMA) is the major component of most soft contact lenses. In a study to evaluate the loading capacity and release characteristics of timolol-imprinted soft contact lenses, a small proportion of me-thacrylic (MAA) or methyl methacrylate (MMA) was added as a functional monomer able to interact through ionic and hydrogen bonds with timolol maleate. MMA is a hydrophobic molecule, polymers of which have been extensively used for non-foldable intraocular lenses. MAA is the parent acid of MMA and is a hydrophilic molecule that is ionized above pH 5.5. Hydrogels were prepared by dissolution of ethylene glycol dimethacrylate, a cross-linker, in HEMA with MMA or MAA and timolol maleate. The results indicate that the incorporation of MAA as co-monomer increases the timolol loading capacity to therapeutically useful levels while sustaining drug release in lacrimal fluid for more than 12 hours, and that the preparation can be reloaded overnight with timolol and ready to use the next day.77,78

Imprinting systems have an enormous potential in pharmaceutical technology, although their applications are still incipient. Current research of applying the molecular imprinting technology to manufacture therapeutic contact lenses focuses on the influence of the backbone monomers on the achievement of the imprinting effect, finding the ideal proportions of the functional monomer and cross-linker constant, and keeping the drug binding site stable.78

1.6.4 Implantable Reservoirs. Implantable reservoirs are devices consisting of a central core of drug encased in layers of permeable and impermeable polymers designed to provide sustained release of the drug when implanted subconjunctivally or intra-vitreally. The device is prepared by compressing a small quantity of an active compound, typically 5-6 mg, in a 2.5-mm tablet die. The pellets are then coated entirely in polyvinyl alcohol (permeable polymer) and ethylene vinyl acetate (impermeable polymer). The device is then heat-treated to change the crystalline structure of the polyvinyl alcohol. The overall release rate is controlled by the layers of ethyl-ene vinyl acetate and polyvinyl alcohol, together with the surface area of the device. The duration and temperature of the heat treatment can also be varied to control the device release rate. Water diffuses into the device to dissolve part of the pellet, forming a saturated drug solution. The device provides a constant rate of release of the active compound.79

The potential advantage of an implantable reservoir is the possibility of delivering the active compound directly into the eye and achieving therapeutic drug concentrations. Constant release of a drug over a long period of time eliminates the need and complication of multiple subconjunctival or intravitreal injections for chronic ocular disorders. Clinical applications of implantable reservoirs have been investigated primarily in four areas: (1) AIDS-associated cytomegalovirus retinitis, (2) chronic uveitis, (3) glaucoma filtering surgery, and (4) proliferative vitreo-retinopathy.

1. Cytomegalovirus retinitis is the most common cause of viral retinitis in patients with AIDS. Intravitreal ganciclovir injection provides a higher intraocular drug concentration in the vitreous than does systemic therapy and a reduced systemic exposure to the drug. However, the relatively short intra-vitreal half-life of ganciclovir requires frequent injections to maintain therapeutic levels in the eye. A ganciclovir intravitreal implant has been developed to provide sustained therapeutic levels in the vitreous for a prolonged period. It is marketed as Vitrasert, a nonerodible drug-delivering implant (figure 1.5). A pellet containing 6 mg of ganciclovir is prepared and coated in polyvinyl alcohol.80 It is designed to release ganciclovir at two rates: 1 and 2 mg/h. The mean release rate calculated from explanted devices designed to release the drug at 1 mg/h was actually 1.9 mg/h. 1 The device was implanted at the pars plana in a 30-minute procedure. It was reported to control cytomegalovirus retinitis in 90% to 95% of cases. Complications include retinal detachment, endophthalmitis, vitreous hemorrhage, and postoperative inflammation.79 When the device becomes depleted, it can be replaced. It can be exchanged after 32 weeks, or earlier if progression of retinitis occurs.81

2. Devices containing cyclosporin A, dexamethasone, or a combination of cy-closporin A and dexamethasone have been prepared and implanted into the vitreous cavity of a rabbit model of uveitis. The devices were reported to be effective in suppressing inflammation.79,82,83

3. Failure of glaucoma filtering procedure is usually due to the proliferation of fibroblasts, which leads to scarring and subsequent blockage of the filter. Subconjunctival injections of 5-fluorouracil (5-FU) have been shown to increase the success rate of glaucoma filtering procedures in patients with poor prognoses. However, multiple injections are required, and there is a high

Bausch And Lomb Iol Model Ma60ac

Figure 1.5. Illustration of position of Vitrasert implant in the vitreous after suturing the device into sclera at the pars plana. The Retisert device can also be implanted in this position. Image provided courtesy Bausch & Lomb Surgical, Inc.

incidence of toxicity to the corneal epithelium and the conjunctival wound. A 5-FU sustained-release device was designed to maintain low therapeutic levels when implanted subconjunctivally. Pellets containing 12 mg of 5-FU were coated in a mixture of permeable and impermeable polymers. When implanted subconjunctivally in the rabbit, the pellet released 5-FU at a rate of approximately 1 mg/day for 10 days. In the phase I clinical study to evaluate the safety and efficacy of the device in high-risk glaucoma surgical patients, the implants were placed subconjunctivally in four patients undergoing trabecu-lectomy. Three of the four patients maintained functioning filters, while the fourth failed within 2 months of surgery. No untoward events were linked to the implant.84 The device is not bioerodible and would remain implanted in the eye indefinitely.

4. An intravitreal implant containing corticosteroid and 5-FU conjugate was studied in a rabbit model of experimental proliferative vitreoretinopathy. The corticosteroids studied included triamcinolone and dexamethasone. Both the intravitreal sustained-release implant containing triamcinolone/5-FU codrug and that containing dexamethasone/5-FU codrug were found to be effective in inhibiting the progression of proliferative vitreoretinopathy in the rabbit model.85,86 Retisert (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile intravitreal implant designed to release fluocinolone acetonide locally to the posterior segment of the eye at a nominal initial rate of 0.6mg/day, decreasing over the first month to a steady state between 0.3 and 0.4 mg/day over approximately 30 months. The implant consists of a fluocinolone acetonide tablet in a silicone elastomer cup containing a release orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The sili-cone cup is attached to a suture tab for surgical implantation into the posterior segment through a pars plana incision. Each implant is approximately 3mm x 2mm x 5 mm. It is indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. Following depletion of flu-ocinolone acetonide from Retisert as evidenced by recurrence of uveitis, it can be replaced. Phase III randomized, double-masked, multicenter-controlled clinical trials showed that the rate of recurrence of uveitis affecting the posterior segment of the study eye ranged from approximately 7% to 14% for a 34-week period postimplantation as compared to approximately 40% to 54% for the 34-week period preimplantation. Based on the clinical trials, within 34 weeks postimplantation, approximately 60% of patients required medications to control IOP. Within an average postimplantation period of 2 years, approximately 32% of patients are expected to require filtering procedures to control IOP, and nearly all phakic eyes are expected to develop

cataracts and require cataract surgery. ,

Implantable reservoirs have been shown to achieve a sustained release of a variety of drugs, particularly in the delivery of drugs into the vitreous cavity. However, risks of endophthalmitis, retinal detachment, vitreous hemorrhage, inflammation, device dislocation or extrusion, cataract formation, and astigmatism have to be extensively studied. At present, the clinical application of these devices is likely to be restricted to sight-threatening diseases requiring long-term drug therapy.

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