CH 3 H3CSiOSiO n Si
7.3 OCULAR IMPLANTS
7.3.4 Ocular Drug Delivery
The diseases in the posterior segment of eye directly impact the patient’s vision and quality of life and are the major cause of blindness in the world . Therefore, biopharmaceuticals are mak- ing increasing impact on medicine for treatment of anterior and posterior diseases of eyes . Conventional ophthalmic drugs delivery system include eye drops, ointments, and gels, which are suitable for treatment of the anterior segment of the eye (cornea, conjunctiva, sclera, and anterior uvea) but not able for treatment of posterior segment of the eyes due to defense mechanisms of the ocular globe as well as anatomical and physiological barriers, static and dynamic barriers in place (Figure 7 .7) . It is found that only a small amount (1%–3%) reaches the intraocular tissue by conventional ocular drug delivery systems (DDSs) [19–122] . Therefore, surgery is opted for the treatment for diseases of the posterior segment as transport of drugs applied by traditional dosage forms cannot be maintained in concentrations in the target tissues for a long duration . Now, with the advancement in science, surgery is less applied by an eye surgeon [121] .
For the treatment of posterior eye diseases, various novel techniques using biodegradable or nonbiodegradable polymer technology system implanted or injected directly into the vitreous, to obtain long-term sustained release of drugs, have been introduced in the market (Figure 7 .8) .
Two types of strategies have been developed for the treatment of anterior and posterior dis- eases namely known as anterior DDSs and posterior DDSs . Anterior DDSs include eye drops (AzaSite® for bacterial conjunctivitis; AzaSite Plus™ for blepharoconjunctivitis; Rysmon® TG for glaucoma; Betoptic S® for glaucoma; TobraDex® ST for blepharitis, Timoptic-XE® for glaucoma;
and Cationorm® for mild dry eye), soft contact lenses (developed by Vistakon Pharmaceuticals, LLC, Philadelphia, PA; and SEED Co ., Ltd ., Tokyo, Japan, with Senju Pharmaceutical Co ., Ltd ., Osaka, Japan which are in clinic trial), Cul-de sac Inserts (Ocusert®, consists of two outer layers of ethylene-vinyl acetate copolymer (EVA), and an inner layer of pilocarpine in alginate gel within di- (ethylhexyl)phthalate for uniform controlled release of pilocarpine drug; Lacrisert®, water soluble rod-shaped insert composed of hydroxypropyl cellulose for dry eyes; and Ocufit SR®, minidisc ocular DDS clinically failure), Punctal Plugs (used for retention time and increase absorption
and efficacy of drugs developed by QLT, Inc ., Vancouver, Canada; and Vistakon Pharmaceuticals, LLC for latanoprost and bimatoprost, respectively), and subconjunctival/episcleral implants (LX201, composed of silicone for release of cyclosporine A for long time; 3T Ophthalmics, a tiny bathtub composed of silicone under clinical trial developed by Irvine, CA; Latanoprost SR insert, composed of a poly(dl-lactide-co-glycolide) (PLGA) tube containing a latanoprost-core and ends are capped with silicon and PVA for release of latanoprost developed by Pfizer, Inc ., New York) [123–135] .
Diseases affecting the posterior eye segment are presently increasing and the treatment of these diseases requires a direct and local application of the agent to the posterior eye seg- ment via topical, subtenon, subconjunctival, scleral, and intravitreal routes . However, the subconjunctival, scleral, and intravitreal routes are effective for controlled prolong release of drug via implants for the posterior eye treatment as they offer direct drug delivery to the tar- get site with minimal systemic loss and can be implanted at the site of vitreous, sclera and subconjunctiva [136] .
Posterior DDSs may be classified as nonbiodegradable, biodegradable, and stimuli-responsive polymeric systems on the basis of polymer used (Figure 7 .9) . Nonbiodegradable polymeric implants are mostly synthesized by polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), and silicon . Nonbiodegradable polymeric implant-based posterior DDSs follow zero order drug release path for effective concentrations release of drug for extended periods of time because they show diffusion controlled release . Due to the hydrophobic nature of silicon and ethylene vinyl acetate- based implants they can be applied for limited drugs whereas PVA-based implants are hydrophilic in nature and can be used for broader range of drugs [137–140] .
Recently, stimuli-responsive polymer-based implants have been developed for drug delivery to the posterior segment of the eye because they show abrupt changes in structure, solubility, charge, volume, and hydrophobic–hydrophilic balance in response to physical or chemical changes in the environment, and release drug at a constant rate on the individual requirements and the disease state [141,142] .
Traditionally they suffer from problems of the low therapeutic response and efficacy .
Therefore, nanocarriers-based strategies have been introduced for improving the residence time and the corneal penetration of ocular drugs because they allow for an increased bioavailability and therapeutic efficacy of ophthalmic drugs, and enhance the permeability of ocular tissues to drugs, provide a specific drug targeting over several hours, reduce or prevent side effects, decrease the frequency of administration, and increase the patient’s adherence to therapy [143–146] .
Tear
Cornea Blood-retinal
barrier
Retina
Barriers in ocular drug delivery
Conjunctiva
Choroid/
Bruch’s
membrane Sclera
Figure 7.7 A schematic representation of barriers in conventional ocular drug delivery systems .
Barriers involved BRB; choroid; and efflux transporters Barriers involved sclera; BRB; and choroid
Systemic delivery Periocular delive
ryIntravitreal delivery (drug is delivered directly to the vitreous chamber)
Topical delivery
Barriers involved cornea and BRB Barriers involved diffusion through the vitreous chamber; neural retina; and blood retinal barrier (BRB)
• Advantages • Better patient compliant • Disadvantages (a) Low bioavailability (b) High doses required (c) Systemic side effects • Advantages (a) Least painful (b) Most efficient route (c) High therapeutic drug levels • Disadvantages (a) Rapid clearance (b) Systemic side effects (c) Tissue hemorrhage
• Advantages (a) Local and direct delivery (b) High therapeutic concentration • Disadvantages (a) Repeat injection, rapid elimination, serious side effects may occur on repetitive injections especially retinal detachment, cataract, vitreous hemorrhage, and endophthalmitis
• Advantages (a) High patient compliance (b) Less systemic side effects • Disadvantages (a) Small retention time (b) Blurring of vision (c) Precorneal drug losses (d) Drainage through the nasolacrimal duct (e) Irritation low bioavailability (choroid and conjunctiva) (majorly via the
transscleral pa
thway)
(corneal, conjunctival, and scleral pathway) Figure 7.8Features of various routes of administration for posterior eye delivery .
Stimuli- responsive implants
Biodegradable
polymeric implan
ts
Nonbiodegradable
polymeric implan
ts
1. Light activated implantable systems (e.g., visudyne activated by nonthermal red laser light to produce single oxygenmolecules that induce coagulation for the treatment of choroidal neovascularization) 2. Conducting polymer-based systems (e.g., polypyrrole (PPy), poly(3,4-ethylenedixoythiophene) (PEDOT), polyaniline and N-methyl pyrrole-based DDSs releasing precise amounts of drug upon electrical 3. Stimulation via a trans-scleral cannula directly into the vitreous 4. Micro electro mechanical system (MEMS)- based implants(consist of one or more drug reservoirs containing either a single drug or multiple drugs in different reservoirs and actuators which are responsible to push the drug out of the reservoir by mechanical means in response to the stimulus) 5. Magnetically modulated implantable systems (composed of one or more polymers with drug and tiny magnets incorporated within the matrix system response to an external magnetic field)
1. Vitrasert(composed of PVA, EVA coating containing 4.5 mg
of ganciclovir for the treatment of CMV retinitis and sutur
ed to the pars plana region of the sclera) 2. Retisert(composed of PVA and silicon coating containing 0.59 mg of fluocinolone acetonide for the treatment of uveitis and sutured to the sclera) 3. Renexus (NT-501) (outer layer composed of polyether sulfone and threaded with polyethylene terephthalate yarnfor secrete recombinant human ciliary neurotrophic factor (CNTF) placed into the vitreous by a small incision in the sclera) 4. Illuvien (composed of PVA matrix containing 190 µg of fluocinolone acetonide for the treatment of diabetic macular edema injected into the vitreous) 1. Ozurdex (composed of PLGA matrix containing 700 µg of dexamethasone fort he treatment of diabetic macular edema and noninfectious uveitis is placed into the vitreous) 2. Verisome (composed of lipid/oil layer containing triamcinolone (IBI-20089) for the treatment of macular edema is placed into the vitreous 3. ENV705(composed of PGA matrix containing trehalose/bevacizumab is placed into the vitreous) Figure 7.9Types of drug delivery systems used for posterior segment drug infections .