title: Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy.
abstract: A prototype multiple-drug delivery implant has been developed for the intraocular management of proliferative vitreoretinopathy (PVR). Because of the recurrent nature of the disease, PVR causes blindness in approximately 7% of patients who have undergone retinal re-attachment surgery. The poly(dl-lactide-co-glycolide) 50/50 (PLGA) implant consists of three cylindrical segments, each of which contains one of the following drugs: 5-fluorouridine (5FUrd, an antimetabolite), triamcinolone (Triam, a corticosteroid), and human recombinant tissue plasminogen activator (t-PA, a thrombolytic agent). The device can be inserted through a 20-gauge syringe needle into the vitreous body of the eye. The implant also possesses a PLGA coating over the t-PA-containing terminal segment, which creates a lag-time to deliver t-PA when most needed and to decrease the risk of postoperative bleeding. Two methods of cylinder fabrication were investigated: heat and solvent extrusion. The release behavior of several drugs was examined as a function of the processing variables including: extrusion method, drug loading, polymer molecular weight, and drug particle size. The presence of either the organic solvent (acetone) during processing or a highly water-soluble drug (5FUrd) in the formulation increased the polymer porosity, which in turn, increased the drug release-rate. Drug loading effects were consistent with percolation concepts, and a low-molecular-weight PLGA (e.g., Mw=42000 for inherent viscosity=0.58 dl/g) was desirable to produce controlled release close to one month. Based on pharmacological and pharmacokinetic data of these compounds and our clinical experience with this disease, several design criteria for a combined implant were devised. Optimal cylindrical segments from the formulation studies were selected and combined in series to form a contiguous implant. After successful combination and coating procedures were developed, prototype implants were prepared. From the 3-drug prototype, 5FUrd and Triam were released approximately 1 microgram/day for over 4 weeks and 10-190 microgram/day over 2 weeks, respectively. The solvent-extrusion procedure did not significantly alter the stability of the encapsulated t-PA (>94+/-5% serine protease activity after preparation). After a lag-time of approximately 2 days, t-PA was released active at a rate of approximately 0.2-0.5 microgram/day in approximately 2 weeks. The release characteristics from the combined implant largely met our initial design criteria. Hence, controlled-release implants of this kind may have potential use for intraocular treatment of PVR.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.forename: H
authors.initials: H
authors.lastname: Lewis
authors.forename: R E
authors.initials: RE
authors.lastname: Foster
authors.forename: S P
authors.initials: SP
authors.lastname: Schwendeman
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004343:Drug Implants; D005123:Eye; D006801:Humans; D008855:Microscopy, Electron, Scanning; D008970:Molecular Weight; D010316:Particle Size; D011108:Polymers; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014221:Triamcinolone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy*
chemical_list: D004343:Drug Implants; D011108:Polymers; D011994:Recombinant Proteins; D014221:Triamcinolone; C001943:5-fluorouridine; D010959:Tissue Plasminogen Activator; D014529:Uridine