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Developing bioequivalent (BE) generic products of complex dosage forms like intravitreal implants (IVIs) of corticosteroids such as dexamethasone prepared using hot-melt extrusion (HME), based on biodegradable poly (lactide-co-glycolide) (PLGA) polymers, can be challenging. A better understanding of the relationship between the physicochemical and physicomechanical properties of IVIs and their effect on drug release and ocular bioavailability is crucial to develop novel BE approaches. It is possible that the key physicochemical and physicomechanical properties of IVIs such as drug properties, implant surface roughness, mechanical strength and toughness, and implant erosion could vary for different compositions, resulting in changes in drug release. Therefore, this study investigated the hypothesis that biodegradable ophthalmic dexamethasone-loaded implants with 20% drug and 80% PLGA polymer(s) prepared using single-pass hot-melt extrusion (HME) differ in physicochemical and/or physicomechanical properties and drug release depending on their PLGA polymer composition. Acid end-capped PLGA was mixed with an ester end-capped PLGA to make three formulations: HME-1, HME-2, and HME-3, containing 100%, 80%, and 60% w/w of the acid end-capped PLGA. Further, this study compared the drug release between independent batches of each composition. In vitro release tests (IVRTs) indicated that HME-1 implants can be readily distinguished by their release profiles from HME-2 and HME-3, with the release being similar for HME-2 and HME-3. In the early stages, drug release generally correlated well with polymer composition and implant properties, with the release increasing with PLGA acid content (for day-1 release, R2 = 0.80) and/or elevated surface roughness (for day-1 and day-14 release, R2 ≥ 0.82). Further, implant mechanical strength and toughness correlated inversely with PLGA acid content and day-1 drug release. Drug release from independent batches was similar for each composition. The findings of this project could be helpful for developing generic PLGA polymer-based ocular implant products.
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Although once daily anti-glaucoma drug therapy is a current clinical reality, most therapies require multiple dosing and there is an unmet need to develop convenient, safe, and effective sustained release drug delivery systems for long-term treatment to improve patient adherence and outcomes. One of the first sustained release drug delivery systems was approved for the reduction of intraocular pressure in glaucoma patients. It is a polymeric reservoir-type insert delivery system, Ocusert™, placed under the eyelid and on the ocular surface for zero-order drug release over one week. The insert, marketed in two strengths, released pilocarpine on the eye surface. While many clinicians appreciated this drug product, it was eventually discontinued. No similar sustained release non-invasive drug delivery system has made it to the market to date for treating glaucoma. Drug delivery systems under development include punctal plugs, ring-type systems, contact lenses, implants, microspheres, nanospheres, gels, and other depot systems placed in the extraocular, periocular, or intraocular regions including intracameral, supraciliary, and intravitreal spaces. This article discusses the advantages and disadvantages of the various routes of administration and delivery systems for sustained glaucoma therapy. It also provides the reader with some examples and discussion of drug delivery systems that could potentially be applied for glaucoma treatment. Interestingly, one intracamerally injected implant, Durysta™, was approved recently for sustained intraocular pressure reduction. However, long-term acceptance of such devices has yet to be established. The ultimate success of the delivery system will depend on efficacy relative to eye drop dosing, safety, reimbursement options, and patient acceptance. Cautious development efforts are warranted considering prior failed approaches for sustained glaucoma drug delivery. Neuroprotective approaches for glaucoma therapy including cell, gene, protein, and drug-combination therapies, mostly administered intravitreally, are also rapidly progressing towards assessment in humans.
Assuntos
Agentes Antiglaucoma , Glaucoma , Preparações de Ação Retardada/uso terapêutico , Sistemas de Liberação de Medicamentos , Glaucoma/tratamento farmacológico , Humanos , Pressão IntraocularRESUMO
Purpose: Reliable drug therapy with injectable intravitreal implants requires implants of consistent quality. The purpose of this study was to prepare dexamethasone-poly(d,l-lactide-co-glycolide) (PLGA) biodegradable implants and assess implant quality within and between batches for different polymer compositions. Methods: Implants containing 20% w/w dexamethasone with 3 theoretical rates of release (fast, intermediate, and slow) were manufactured with decreasing proportion of acid-terminated PLGA (50:50) and increasing proportion of ester-terminated PLGA (50:50) in a batch process using hot-melt extrusion. The implants were manufactured without and with in-process modification of extrusion/conveyor speed in the late phase of each batch. Implant samples collected at early, middle, and late phases of each batch were analyzed for diameter, drug loading, mechanical properties (strength and toughness), and drug release. Results: With a fixed process, unlike a modified process with an increase in extrusion speed and reduction of conveyor speed in the late phase, all implant formulations tended to decrease in diameter and mechanical properties in the late phase. Drug release profiles for the intermediate and slow release compositions were similar with or without process modification, unlike the fast release composition. Addition of ester-terminated PLGA resulted in a slower drug release. When all formulations are grouped together, the implant diameter exhibited a moderate correlation with mechanical properties, but no correlation was observed with drug release. Conclusions: Within a hot-melt extrusion batch process, the dexamethasone-PLGA implant diameter and hence toughness and strength tend to decline in the latter phase. In-process adjustment of extrusion and conveyor speeds can improve batch consistency and, potentially, implant integrity or performance during or after injection. Process changes did not affect drug release for 2 of the 3 implant compositions.
Assuntos
Dexametasona/farmacocinética , Tecnologia de Extrusão por Fusão a Quente/métodos , Bombas de Infusão Implantáveis/estatística & dados numéricos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Implantes Absorvíveis/efeitos adversos , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/farmacocinética , Preparações de Ação Retardada/química , Dexametasona/administração & dosagem , Composição de Medicamentos/métodos , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos/fisiologia , Oftalmopatias/patologia , Humanos , Inflamação/tratamento farmacológico , Bombas de Infusão Implantáveis/efeitos adversos , Injeções Intravítreas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Reprodutibilidade dos TestesRESUMO
Even though the very thought of an injection into the eye may be frightening, an estimated 6 million intravitreal (IVT) injections were made in the USA during 2016. With the introduction of new therapeutic agents, this number is expected to increase. In addition, drug products that are injectable in ocular compartments other than the vitreous humor are expected to enter the back of the eye market in the not so distant future. Besides the IVT route, some of the most actively investigated routes of invasive administration to the eye include periocular, subretinal, and suprachoroidal (SC) routes. While clinical efficacy is the driving force behind new injectable drug product development for the eye, safety is also being improved with time. In the case of IVT injections, the procedural guidelines have evolved over the years to improve patient comfort and reduce injection-related injury and infection. Similar advances are anticipated for other routes of administration of injectable products to the eye. In addition to procedural improvements, the design of needles, particularly those with smaller diameters, length, and controlled bevel angles are expected to improve overall safety and acceptance of injected ophthalmic drug products. A key development in this area is the introduction of microneedles of a length less than a millimeter that can target the SC space. In the future, needles with smaller diameters and lengths, potentially approaching nanodimensions, are expected to revolutionize ophthalmic disease management.