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Evolving trend of drug delivery system


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Evolving trend of drug delivery system

  1. 1. www. l 67 Uvea www. l 67 Uvea(YROXWLRQ Pranita Sahay MBBS EvolvingTrend of Drug Delivery System in Uveitis Pranita Sahay MBBS, Devesh Kumawat MBBS, Koushik Tripathy MD, DNB, Vijay Kumar Sharma MS Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi Uveitis is an umbrella term that includes any KPƀCOOCVQT[ RTQEGUU VJCV RTKOCTKN[ CHHGEVU VJG WXGCN tissue. It may be anterior, intermediate, posterior or panuveitis. Intermediate, posterior uveitis, and panuveitis are the most sight threatening types of uveitis. If no infectious microbe is implicated in the disease process then it is said to be idiopathic and treatment is aimed at UWRRTGUUKPI VJG KPƀCOOCVQT[ RTQEGUU $[ HCT VJG OQUV EQOOQP ENCUU QH FTWI VQ SWGPEJ VJG KPƀCOOCVQT[ ſTG of uveitis is corticosteroids which can be administered in various forms- oral, intravenous, topical drops, periocular injection, intravitreal injection or intraocular implants. Immunosuppressive agents and immunomodulators are the other class of drugs used in the management of idiopathic uveitis. Long term use of systemic corticosteroids and immunomodulators have high risk of systemic adverse effects and topical medication have poor penetration to the posterior segment of eye. This has lead to a new era of invention of sustained drug delivery system1 . Retisert® Introduced by Bausch and Lomb (Rochester, NY, USA) in 1951, it is a non biodegradable, sustained release KPVTCXKVTGCN KORNCPV QH ƀWEKPQNQPG CEGVQPKFG OI +V JCU been FDA-approved (Food and Drug Administration, USA) for chronic macular edema due to chronic non infectious posterior uveitis2 . Retisert is about the size of a grain of rice and consists of a tablet encased in a silicone elastomer EWR EQPVCKPKPI C TGNGCUG QTKſEG CPF C 2QN[XKP[N CNEQJQN (PVA) membrane positioned between the tablet and the QTKſEG 6JG UKNKEQPG GNCUVQOGT EWR CUUGODN[ KU CVVCEJGF VQ a PVA suture strut with silicone adhesive. It is implanted into the vitreous cavity by par plana incision and then suturing. The drug is delivered at initial rate of 0.6 μg/day, FGETGCUKPI QXGT VJG ſTUV OQPVJ VQ C UVGCF[ UVCVG DGVYGGP 0.3 to 0.4 μg/day with no drug peaks and troughs, and it lasts for approximately 1,000 days (30 months). During clinical trials it has shown to decrease the recurrence of episode from 54 % to 7% and 40% to 14% in two different trials and also either stabilisation or an increase in visual acuity in 80% patients was noted. The common ocular adverse effects with Retisert are raised intraocular pressure and cataract. MUST trial (Multicenter Uveitis Steroid 6TGCVOGPV GXCNWCVKPI KVU GHſECE[ KP WXGKVKU XGTUWU U[UVGOKE CPVKKPƀCOOCVQT[ VJGTCR[ UJQYGF VKOGU KPETGCUG KP glaucoma and 3.3 times increased cataract surgery rate3 . Rare but the most dreaded one being endophthalmitis. Another major disadvantage with Retisert is that it can’t be KORNCPVGF KP CP QHſEG RTQEGFWTG (KIWTG Iluvien® Iluvien® (formerlyMedidurFA,AlimeraSciences,Alpharetta, GA, USA) is a non biodegradable intravitreal implant of ƀWEKPQNQPG CEGVQPKFG zI +V EQPUKUVU QH C E[NKPFTKECN polyimide tube, 3.5mm in length and 0.37mm in diameter. Unlike Retisert however, Iluvien® is injected into the eye CU CP QHſEG DCUGF RTQEGFWTG WUKPI C RTQRTKGVCT[ KPUGTVGT with a 25-gauge needle, which allows a self sealing wound. Figure 1: Retisert
  2. 2. 68 l DOS Times - Vol. 20, No. 3 September, 2014 Evolution: Evolving Trend of Drug Delivery System in Uveitis The method of administration is similar to an intravitreal KPLGEVKQP +V JCU DGGP J[RQVJGUKGF VJCV ƀWQEKPQNQPG acetonide (FAc) inserts may cause fewer problems with glaucoma than the surgically implanted device because QH NQYGT KP XKVTQ TGNGCUG TCVGU QH ƀWQEKPQNQPG CEGVQPKFG (0.2 and 0.5μg/day for at 24-36 months and 18 months respectively) and also because of a more posterior location in the eye, which may decrease exposure to the trabecular meshwork in the anterior chamber while still delivering CFGSWCVG NGXGNU QH ƀWQEKPQNQPG CEGVQPKFG VQ VJG TGVKPC (Figure 2). Three year results of FAME study (Fluocinolone Acetonide Implant Compared to Sham Injection in Patients With Diabetic Macular Edema) showed that by 36 months, 80-90% patients in FAc groups required cataract surgery versus 27.3% of phakic controls. Approximately 20% of patients in FAc groups experienced an intraocular pressure (IOP) more than 30 mm Hg at any point in the study compared to 4.3% of sham control patients; 5-8% of patients in FAc groups required IOP-lowering surgery compared to 0.5% for controls, respectively4 . Surodex® Surodex produced by Allergan(Allergan, Irvine, CA, USA) is a rod-shaped biodegradable matrix implant of dexamethasone and poly lactideco- glycolide acid (PLGA) with hydroxypropyl methylcellulose (HPMC). It is 1.0×0.5 mm in size and has a drug release rate of 60 μg over 7–10 days. It is implanted into the anterior chamber following ECVCTCEV UWTIGT[ VQ EQPVTQN VJG RQUVQRGTCVKXG KPƀCOOCVKQP5 . Ozurdex® Ozurdex is produced by Allergan, Irvine, CA, USA is also called Posurdex during trials. It is a biodegradable intravitreal implant of dexamethasone 0.7 mg. The Novadur™ drug delivery system containing poly (D, L- lactide-co-glycolide) without preservative, degrades slowly to lactic acid and glycolic acid. It has a preloaded single- use specially designed applicator to facilitate the injection of a rod-shaped implant directly into the vitreous cavity. It is delivered via surgical sclerotomy or 22-gauge needle- injector system. Its effect lasts for 6 months. Its adverse effect being raised intraocular pressure which peaks at around 60 days. Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber. It is currently FDA approved for central and branch retinal vein occlusion, non infectious uveitis affecting the posterior segment and diabetic macular oedema. HURON study is evaluating its role in macular edema in posterior Uveitis (Figure 3). Vitrasert It is produced by Bausch and Lomb (Rochester, NY, 75# CPF KU VJG ſTUV KORNCPVCDNG ICPEKENQXKT FGNKXGT[ device approved by the FDA in 1996 for treatment of cytomegalovirus (CMV) retinitis. Human viruses sensitive to ganciclovir include cytomegalovirus (CMV), herpes Figure 2: Iluvein Figure 3: 2]XUGH[
  3. 3. www. l 69 Uvea simplex virus-1 and -2 (HSV- 1, HSV- 2), Epstein - Barr virus (EBV) and varicella zoster virus (VZV). The device is composed of drug and polymeric coats of polyvinyl alcohol (PVA) and ethylenevinyl acetate (EVA). PVA is a permeable polymer that regulates the rate of ganciclovir release and EVA is an impermeable polymer that limits the surface area of the device through which the active agent can be released. Each implant contains around 4.5 mg to 6.4mg of ganciclovir. It releases the drug at mean rate of 1.4μg/day and a mean vitreous concentration of 4.1μg/ml is achieved. The device has shown to have no initial burst effect. The commercially available device is relatively large; it requires a 4–5mm sclerotomy at the pars plana for implantation. It releases the drug for 5 to 8 months. Since it is nonbiodegradable the drug-depleted device needs to be removed during a second procedure in order to implant another device if required (Figure 4). Iontophoresis It uses electrical current to facilitate delivery of medication or ions into the tissue for therapeutic purposes based on the physical principle that like charges repel each other. Eye gate (Optis Group, Paris, France) and OcuPhor (IOMED, Salt Lake City) are two ophthalmic iontophoresis systems under investigation. EGP-437 (dexamethasone phosphate formulated for iontophoresis) is being evaluated for non- infectious anterior uveitis (Figure 5). Contact Lens Contact lenses can absorb drugs and release over a period of time. Silicon-hydrogel contact lens loaded with vitamin E has been shown to increase dexamethasone release period from 1 day to 7 - 9 days6 . Nanoparticles They have the ability to penetrate tissue better, resulting in more controlled release of drug over longer duration. Figure 4: Vitrasert Tamoxifen-loaded nanoparticles injected intravitreally have been shown to be effective in treating experimental autoimmune uveitis (EAU) models whereas non- encapsulated tamoxifen had no effect7 . Betamethasone- encapsulated particles have successfully treated experimental autoimmune uveoretinitis models8 . However further reasearch is warranted to discover newer avenues of treating uveitis. References 1. Nahid Haghjou, Masoud Soheilian, Mohammad Jafar Abdekhodaie, Sustained Release Intraocular Drug Delivery Devices for Treatment of Uveitis. Journal of ophthalmic and vision research 2011;4: 317- 29. 2. Jaffe GJ, Martin D, Callanan D. Fluocinolone acetonide implant (Retisert) for non-infectious posterior uveitis. Ophthalmology 2006;113:1020-27. 3. Kempen JH, Altaweel MM, Holbrook JT. Randomized comparison QH U[UVGOKE CPVKKPƀCOOCVQT[ VJGTCR[ XGTUWU ƀWQEKPQNQPG acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial [MUST]. Ophthalmology 2011;10:1916–26. #PVQU[M #0 (#/' +PXGUVKICVQTU 'HſECE[ CPF 5CHGV[ QH +.78+'0 4 (Fluocinolone Acetonide [FAc] Intravitreal Insert) for the Treatment of Diabetic Macular Edema. ARVO Meet Abstr 2011;52:6645. .GG 5; %JGG 52 5WTQFGZ CHVGT RJCEQGOWNUKſECVKQP , %CVCTCEV Refract Surg 2005;31:1479–80. 6. Kim, J, Peng CC, Chauhan A. Extended release of dexamethasone from silicone-hydrogel contact lenses containing vitamin E. J Control Rel. 2010; 148:110-16. 7. De Kozak Y, Andrieux K, Villarroya H. Intraocular injection of tamoxifen-loaded nanoparticles:A new treatment of experimental autoimmune uveoretinitis. Eur J Immunol. 2004; 34:3702-12 8. Sakai T, Kohno H, Ishihara T, et al. Treatment of experimental autoimmune uveoretinitis with poly(lactic acid) nanoparticles encapsulating betamethasone phosphate. Exp Eye Res. 2006; 82:657-63. Figure 5: 2FX3KRU LRQWRSKRUHVLV VVWHP $SSOLFDWRU LV SODFHG over the sclera under the lower eyelid