Cyclosporine A delivery to the eye: a pharmaceutical challenge.

Systemic administration of cyclosporine A (CsA) is commonly used in the treatment of local ophthalmic conditions involving cytokines, such as corneal graft rejection, autoimmune uveitis and dry eye syndrome. Local administration is expected to avoid the various side effects associated with systemic delivery. However, the currently available systems using oils to deliver CsA topically are poorly tolerated and provide a low bioavailability. These difficulties may be overcome through formulations aimed at improving CsA water solubility (e.g. cyclodextrins), or those designed to facilitate tissue drug penetration using penetration enhancers. The use of colloidal carriers (micelles, emulsions, liposomes and nanoparticles) as well as the approach using hydrosoluble prodrugs of CsA have shown promising results. Solid devices such as shields and particles of collagen have been investigated to enhance retention time on the eye surface. Some of these topical formulations have shown efficacy in the treatment of extraocular diseases but were inefficient at reaching intraocular targets. Microspheres, implants and liposomes have been developed to be directly administered subconjunctivally or intravitreally in order to enhance CsA concentration in the vitreous. Although progress has been made, there is still room for improvement in CsA ocular application, as none of these formulations is ideal

Biological conversion of a water-soluble prodrug of cyclosporine A

UNIL088 is a water-soluble prodrug of cyclosporine A (CsA) designed for topical ocular delivery. The pro-moiety is grafted via an ester function to CsA and the solubilizing group is a phosphate ion. The aim of this study was to elucidate the conversion mechanisms by which UNIL088 generates CsA. UNIL088 was incubated in rabbit tears at physiological temperature to study its enzymatic and chemical conversion, respectively. Metabolites and intermediates were identified using a quadrupole-time of flight (QqTOF) mass spectrometer, which allowed biotransformation pathways to be deduced. Conversion is activated by the chemical or enzymatic hydrolysis of the terminal ester function of the pro-moiety, leading to the phospho-serine-sarcosine-cyclosporine A that spontaneously converts into CsA. In addition to the main biotransformation pathway, a secondary reaction involved hydrolysis of the phosphate ester group of the pro-moiety, probably by phosphatases present in tears

Conversion of cyclosporine A prodrugs in human tears vs rabbits tears

The aim of this study was to evaluate the rate and mechanism of conversion of two water-soluble prodrugs of cyclosporine A (CsA) intended for topical delivery to the eye. The new molecules were designed according to the double prodrug concept: a solubilizing moiety was grafted onto CsA via an ester function, which could be hydrolysed via a two-step process (enzymatic and chemical). Prodrug solutions were prepared extemporaneously in an isotonic and neutral aqueous medium compatible with ophthalmic use. The rates of conversion into the parent molecule were determined by incubating the prodrugs in fresh rabbit or human tears or in a phosphate buffer solution (PBS) at pH 7.4. Both prodrugs were converted into CsA within the first minute in the presence of rabbit tears with rate constants of k = 5.9 X 10(-3) min(-1) and k = 3.8 X 10(-3) min(-1), respectively, for UNIL088 and UNIL089, whereas chemical conversion in PBS was negligible (k = 0.5 X 10(-3) min(-1) for both molecules). Incubation of UNIL088 in human tears showed a significantly high conversion rate. It is concluded that the developed double prodrugs underwent a bioconversion in physiological media and thus represent promising candidates for topical delivery of CsA to the eye. (C) 2004 Elsevier B.V. All rights reserved

Biodegradable scleral implants as new triamcinolone acetonide delivery systems

The goal of this study was to develop ocular scleral implants able to release triamcinolone acetonide (TA) overall several months. Scleral discs were manufactured by a compression-molding method using a new synthetic polymer, poly(methylidene malonate) (PMM2.1.2), as matrix. Implants with good mechanical properties adapted for in vivo implantation have been obtained when using high M(w) PMM2.1.2 (100,000 - 150,000 Da) associated with ethoxylated derivatives of stearic acid (Simulsol) or oligomers of methylidene malonate as plasticizer. After implantation in rabbit eyes, scleral implants showed a good ocular biocompatibility. Indeed, the clinical follow-up and ocular inflammation parameters, such as inflammatory cell number and protein content in aqueous humor, demonstrated that implants were well tolerated and did not provoke abnormal inflammation. Implants were able to release significant concentrations of TA in the vitreous and the sclera throughout 5 weeks

Polymers in Ophthalmology

El articulo Polymers in ophthalmology es parte del capitulo 6 del libro Advanced polymers in medicine.Ophthalmological sciences are disciplines focused in the health of the eyes and related structures, as well as vision, visual systems, and vision information processing in humans; dealing with the anatomy, physiology and diseases of the eye. Along time a wide variety of materials, including metals, ceramics and polymers, have been developed and used in different ophthalmic applications. Although, modern ophthalmic devices and drug platforms are made with polymeric materials. Applications of polymers in ophthalmology include vitreous replacement fluids, contact lenses, intraocular lenses, artificial orbital walls, artificial corneas, artificial lacrimal ducts, glaucoma drainage devices, viscoelastic replacements, drug delivery systems, sclera buckles, retinal tacks and adhesives, and ocular endotamponades. Both synthetic and natural polymeric biomaterials are used in ophthalmological applications, although in the lasts years most efforts were focused in natural and biocompatible materials, such as gelatin, hyaluronan, chitosan, gums, etc.; developing, tablets, films, suspensions, nanosystems, inserts, etc. This chapter attempts to offers an insight into the importance of polymers in the design and development of pharmaceuticals platforms used in ocular therapeutics.Fil: Calles, Javier Adrián. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina.Fil: Bermudez, José María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Investigaciones para la Industria Química; Argentina.Fil: Bermudez, José María. Universidad Nacional de Salta. Facultad de Ingeniería. Instituto de Investigaciones para la Industria Química; Argentina.Fil: Valles, Enrique Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Bahía Blanca; Argentina.Fil: Valles, Enrique Marcelo. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; ArgentinaFil: Allemandi, Daniel Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina.Fil: Allemandi, Daniel Alberto. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina.Fil: Palma, Santiago Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina.Fil: Palma, Santiago Daniel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina.Otras Ciencias Química