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Figura 9. Tabla 1. Tabla 2. Una vez finalizado el programa de entrenamiento se Rangos. Optometric management of learning-related vision problems St. Louis: Mosby, Atchison et al. Cuestionario 1. The posible effect of under correctionon myopic progression in children. Clin Exp Optom. Sep ;89 5 J Am Optom Assoc. Inducing myopia, hyperopia, and astigmatism in chicks.

Optom Vis Sci. Walline, j. Choroidal and scleral mechanisms of compensation for spectacle lenses in chicks. Vision Res. Mientras que el bloque de poli-oxietileno EO tiene la afinidad por el material de silicona, el bloque de poli-oxibutileno BO tiene afinidad por el agua.

Rumpakis JMB. New data on contact lens dropouts: an international perspective. Rev Optom. Characterization of ocular surface symptoms from optometric practices in North America. Cornea ; Guillon M, Maissa C. Dry eye symptomatology of soft contact lens wearers and nowearers.

Responses of contact lens wearers to a dry eye survey. Optom Vis Sci ; A patient questionnaire approach to estimating the prevalence of dry eye symptoms in patients presenting to optometric practices across Canada. Dryness symptoms among an unselected clinical population with and without contact lens wear.

Cont Lens Anterior Eye ; Discontinuation of contact lens wear: a survey. Int Contact Lens Clin A lens care solution designed for wetting silicone hydrogel materials.

Chemical and frictional analysis of silicone hydrogel contact lens surfaces. Antibacterial, antifungal and antiamoebal properties of a novel multi-purpose solution. Invest Ophthalmol Vis Sci. Broad spectrum antimicrobial activity of a new multi-purpose disinfecting solution. CLAO J. Antimicrobial spectrum of a new contact lens disinfectant.

December Aspects of the antimicrobial mechanisms of a polyquaternium and amidoamide. Journal of Antimicrobial Agents and Chemotherapy. CLS, September Meadows, David, PhD. Fig 1. Fig 2. Fig 3. Estamos en contacto. Referencias 1. Arita, R. Itoh, K. Inoue, A. Kuchiba, T. Yamaguchi, and S. Amano, Contact lens wear is 2. Ophthalmology, Itoh, S. Maeda, K. Maeda, A.

Furuta, S. Fukuoka, A. Tomidokoro, and S. Amano, Proposed diagnostic criteria for obstructive meibomian gland dysfunction. Furuta, A. Amano, Meibomian gland duct distortion in patients with perennial allergic conjunctivitis.

Cornea, Amano, Efficacy of diagnostic criteria for the differential diagnosis between obstructive meibomian gland dysfunction and aqueous deficiency dry eye. Japanese Journal of Ophthalmology, Nichols, J. Berntsen, G. Mitchell, and K. Nichols, An assessment of grading scales for meibography images. Henriquez, A. Korb, Meibomian glands and contact lens wear.

British Journal of Ophthalmology, Korb, D. Henriquez, Meibomian gland dysfunction and contact lens intolerance. Journal of the American Optometric Association, Ong, B. Larke, Meibomian gland dysfunction: some clinical, biochemical and physical observations.

Ophthalmic and Physiological Optics, Hom, M. Martinson, L. Knapp, and J. Paugh, Prevalence of meibomian gland dysfunction. Optometry and Vision Science, Marren, S. Sinnott, Tear film, contact lens, and patient factors associated with corneal staining. Investigative Ophthalmology and Visual Science, En , esa cifra puede superar 2. AMD Alliance International. Instituto Mexicano del Seguro Social.

Por lo que se propone seguir trabajando en este tipo de investigaciones para beneficio de la salud ocular del trabajador. La Occupational Safety and Health Administration OSHA , resalta la importancia de los optometristas para orientar y educar sobre las reglas de la seguridad de los ojos y de los dispositivos protectores.

Instrumentos utilizados: 1. El trabajo precario de las maquiladoras, la falta de seguridad social y los bajos salarios provocan una gran movilidad en este tipo de empresas lo que complica conocer el verdadero estado de morbilidad en estos trabajadores. Herramientas para el estudio de la nocividad laboral en defensa de la salud en el trabajo.

Noriega, M. Cruz, J. Forrest, K. Ledesma, B; Pulido, M. Mittal, S; Mittal. A; Rengappa R. Julio -Agosto, Vol. Salinas, J. Afecta aproximadamente a una de cada 10, personas, con mayor prevalencia en personas con alteraciones oculares y albinismo.

El resultado es un nistagmus horizontal. Nistagmus vestibular central: Se presenta en lesiones del tallo cerebral y da como resultado Nistagmus vertical. Los globos oculares parecen converger y retraerse durante cada fase, se observa mejor cuando el paciente ve hacia abajo. Divido en dos secciones, un parte para marcas propias, y otra que corresponde a las licencias distribuidas por Safilo, el recorrido por el showroom permite pasar por una amplia gama de opciones para vestir la mirada.

Desde detalles como el uso de cristales Swarovski engarzados a las varillas, hasta acetatos coloridos que simulan finas mascadas y monturas bicolor de gran formato en llamativas tonalidades.

El Prof. Son mujeres cuyo profesionalismo y estilo transmiten un mensaje de creatividad, frescura y empoderamiento accesible a todo el mundo. Formas distintivas y acabados sutiles mate dan vida al concepto de modelos con elegancia de vida esencial. Una gafa solar femenina con la exclusiva firma del Sr. Varillas rectas de aluminio con piezas de suave piel en su cara interna, realzan el toque sofisticado de los ricos acetatos de los frentes.

La masculina paleta de color incluye negro, gris, azul ten todos los modelos, tanto vista como sol. Sus colecciones se han convertido en referentes de la moda tanto para hombres como para mujeres.

Vision Expo ha trabajado para crear un concepto de evento espectacular, que resulte ideal para los asistentes, facilite su estancia en el encuentro y aumente la posibilidad de crear un gran ambiente de negocios. Esta actividad, en la que participaron prensa y compradores internacionales, forma parte de un plan para difundir las oportunidades de Italia como destino de negocios. Los resultados y el gran aforo conseguido fueron producto del trabajo del equipo que lidera el Lic.

Prefiero hacer las cosas a mi manera. A veces me resisto a pedir ayuda Si se necesita hacer cambios, estoy en todo. No quiero sorpresas. Me doy un espacio para analizar errores. Para evaluar el ojo derecho, pedir al paciente que mire hacia su oreja derecha o sobre su hombro derecho. A "release profile," as in "defined release profile," refers to a release rate as a function of time of the therapeutic agent from a plug of the invention to the eye, which can be defined or determined by selection of a polyurethane polymer or copolymer for a particular therapeutic agent.

The release profile in turn will govern both the concentration of the agent in the eye and the surrounding tissue during the period of time during which the cap releases the agent. Detailed description The implants release the agent to a surrounding eye or tissue, or both, for a period of time, for treatment of a condition in the patient for which the use of the therapeutic agent is medically indicated.

The implant is adapted for disposition within or adjacent to a patient's eye, to provide sustained release of a therapeutic agent to the eye or surrounding tissues or both. The sheath body is disposed on a portion of the drug core to inhibit the release of the agent from said portion and such that it defines at least one exposed surface of the drug core adapted to release the agent to the surrounding eye or tissue, or both, when the implant is inserted into the patient.

The exposed surface of the nucleus is adapted to release therapeutic amounts of the agent in tissues or body fluids, for example in the tear fluid, for a period of time of at least several days inside the tear fluid when the implant is inserted. For example, when the drug itself is disposed within an implant inserted into the eye canaliculus, the sheath acts to inhibit the release of the agent to the therapeutic target, for example, the eye, while blocking the release to non-target tissue, such like the inside of the cannula, or the nasal sinus.

In one embodiment, the drug core may be substantially cylindrical in shape, having an axis, wherein the exposed surface of the drug core is disposed on an end of the cylindrical shape and a surface of the drug core covered by the body of the sheath constitutes a rest of the surface of the cylindrical shape.

Five fifty 55 The agent released by each of the drug inserts is similar from one insert to another. In some embodiments, among a plurality of drug inserts, the therapeutic amount of the agent released by each of the plurality of the inserts may be the same.

The drug core or drug insert may have various relative contents of the therapeutic agent in them. For example, the drug core may include about 0. The sheath is formed from a substance impermeable to the drug to block the release of the agent except through an exposed surface. It can be formed of any suitable biocompatible material, such as a polymer comprising at least one of polyimide, PMMA, or PET, wherein the polymer is extruded or molten; or a metal comprising stainless steel or titanium.

A therapeutic agent for use in the insert or core of the invention may include antiglaucoma medications eg, adrenergic agonists, adrenergic antagonists beta blockers , carbonic anhydrase inhibitors CAIs, systemic and topical , parasympathomimetics, prostaglandins such as latanoprost and hypotensive lipids, and combinations thereof , antimicrobial agents for example, antibiotics, antiviral, antiparasitic, antifungal, etc.

Additional agents that may be used with these implants include, but are not limited to, drugs that have been approved under section of the United States Federal Food, Drug, and Cosmetic ACT or under Public Health. In various embodiments, an agent may be cyclosporine, or a prodrug or derivative thereof, or olopatadine, or a prodrug or derivative thereof, and optionally, a second agent selected from the therapeutic agents listed above.

In addition, the concentration of the therapeutic agent in a volumetric portion of the drug core may be the same as any other equal volumetric portion of the drug core, in certain embodiments including those embodiments where the agent is present as a uniform, homogeneous dispersion and in embodiments where the agent is present in solid or liquid inclusions throughout the matrix.

In various embodiments, the agent can be dissolved in the matrix within the drug core, that is, at an effective concentration for use as an implant, wherein the agent is sufficiently soluble in the polymer such that inclusions or concentrated agent domains.

This is known in the art as a solid solution, that is, a uniform, homogeneous dispersion at the molecular level, where the solid polymer plays the role of a solvent, and no liquid solvent is present. In various embodiments, the agent is insufficiently soluble in the matrix to form a solid solution. As discussed above, the size and size distribution of the inclusions can have an effect on the rate of release of the agent from the drug core to the patient.

For example, smaller, more uniform inclusions can serve to infuse the matrix in volume with the agent more effectively, at a higher rate, due to a more favorable surface area to volume ratio.

In accordance with the foregoing, the methods of the invention provide for the control or regulation of the average inclusion diameter or the distribution of the inclusion diameters. In various embodiments, the distribution of the diameters of the inclusions may be a monodisperse distribution.

In various embodiments, the inclusions predominantly comprise a cross-sectional size within a range of about 0. It is believed that narrow, or monodisperse, distributions of inclusion diameters are favorable from the point of view of the therapeutic aspects of the drug core or of a drug insert containing the core.

In various embodiments, the drug insert or drug core may comprise two or more therapeutic agents, or may comprise a plurality of drug cores. Such a plurality of drug cores can also be referred to as a plurality of drug sub-cores which together form the total drug core. In this context, first and second drug cores can also be called first and second drug sub-cores for clarity purposes.

For example, a drug insert may include two drug cores disposed within the body of the sheath, a first drug core comprising a first agent and a first matrix, and a second drug core comprising a second agent and a second matrix, wherein the first agent and the second agent are different, and where the first matrix and the second matrix are the same or different from each other; the implant body comprising an opening adapted to receive the first and second cores arranged inside the sheath body, the drug cores being adapted to be disposed, within the sheath, within the opening of the implant body.

The first matrix and the second matrix may differ from each other with respect to at least one of composition, an exposed surface area, a surfactant, a crosslinking agent, an additive, a matrix material, a formulation, a modifying reagent the release rat, or a stability.

The first drug core and the second drug core may be disposed within the sheath body such that the first drug core has a surface disposed directly to the tear fluid and the second drug core does not have a surface disposed directly to the liquid tear When the drug insert is disposed within the implant body and the implant body is disposed in or adjacent to the patient's eye.

Or, the first drug core and the second drug core may be arranged side by side within the body of the sheath. Or the first drug core and the second drug core may each be cylindrical in shape and be disposed within the sheath body, the first drug core being positioned close to a proximal end of an opening in the implant body and the second drug core being positioned close to a distal end of the opening, where the drug insert is disposed within the implant body.

Or, the first drug core and the second drug core can each be cylindrical in shape, provided that the first drug core has a first central opening, the drug cores being positioned concentrically within the body of sheath within an opening of the implant body adapted to receive the drug insert, and the second drug core being configured to fit within the first central opening of the first drug core. Or, the first and second drug cores may be concentrically positioned within the implant body opening, the first drug core having a first central opening that exposes a first internal surface and the second drug core having a second opening central that exposes a second internal surface, the second drug core being configured to fit within the first central opening of the first drug core, and wherein the opening extends from a proximal end to a distal end of the implant body being adapted therefore to allow the tear fluid to pass through the opening and come into contact with the first and second inner surface of the first and second central openings and release the first and second therapeutic agents into the patient's canaliculus where the body of the Implant is inserted in a patient.

In various embodiments, the first therapeutic agent may have a release profile where the first agent is released at therapeutic levels over a first period of time and the second therapeutic agent may have a second release profile where the second agent It is released at therapeutic levels over a second period of time.

For example, the first period of time and the second period of time may be between one week and five years. The first release profile and the second release profile may be substantially the same, or they may be different.

In various embodiments, the first agent can provide a first effect and a side effect to the patient, and the second agent can provide a second effect that mitigates or counteracts the side effect of the first agent.

The implant body may comprise a central hole that extends from a proximal end to a distal end of the implant body such that it is adapted to allow a tear fluid to pass through the implant body such that the first and Second therapeutic agents are released into the tear fluid in a patient's canaliculus when the implant body is disposed in or adjacent to the eye. The drug insert or the drug core may additionally include a porous material impregnated with medication within the first matrix, the second matrix, or both, wherein the porous material impregnated with the medication is adapted such that it allows the liquid tear free the first agent, the second agent, or both, from the porous material impregnated with the medication at therapeutic levels for a sustained period when an implant containing the drug core is disposed within a point or within a tear canaliculus, and wherein the porous material impregnated with the medication is a gel material that can swell from a first diameter to a second diameter when in contact with the tear fluid.

An example of a suitable material for the porous material impregnated with the medication is the hydrophilic hydroxy ethyl methacrylate polymer HEMA. The implant can be a tear implant inserted into a tear canaliculus, which is commonly referred to as a tear point plug, that is, an implant adapted for insertion through a point of the eye to receive into the eye canalicle, where the Drug insert may come into contact with the tear fluid and therefore release the therapeutic agent to come into contact with the eye or surrounding tissues or both.

The core of the insert comprises the agent and a matrix, the matrix comprising a polymeric material, surrounded by a sheath body. The sheath body is substantially impermeable to the agent, such that the agent is released to the tear fluid only through an exposed surface of the core that comes into contact with the tear fluid. The agent contained within the nucleus serves as a reservoir in order to release therapeutic amounts or concentrations of the agent over a period of time, which may vary from days to months.

For example, in the treatment of glaucoma, the drug insert may contain a prostaglandin analog such as latanoprost. The drug core is adapted to be disposed within a larger structure, an implant, which in turn is adapted to be disposed within the tissue, cavity or body duct.

In various embodiments, the implant may be a tear-shaped stopper adapted for placement within the eye canaliculus, that is, within the duct or ducts that drain tears from the surface of the eye.

For example, drug cores may be used in implants, such as a tear-shaped stopper, adapted for placement near the eye to treat a patient suffering from an eye condition through the release of one or more drugs from the nucleus inside the implant on the surface of the eye, such as by diffusion to the tear fluids.

Also, the implants of the invention with their cores can be used for the release of therapeutic agents in tissues, body cavities, or ducts, other than an eye or adjacent structures.

In various embodiments, a drug core comprising a composition of a therapeutic agent of a matrix is partially contained within or surrounded by a sheath, the sheath being substantially impermeable to the agent.

The sheath may cover part, but not all, of the surface of the core comprising the drug and the matrix material, the core having an exposed surface such that the therapeutic agent can be released therethrough. The sheath may be composed of any suitable biocompatible material that is substantially impermeable to the therapeutic agent.

For example, the sheath may be an impermeable polymeric material such as a polyimide, polymethyl methacrylate, or a polyester such as PET or a biocompatible metal such as stainless steel or titanium, or an inorganic glass, such as formed from oxide of silicon.

The agent can be any therapeutic substance capable of at least some diffusion through the matrix. Other substances, such as release rat modifying substances such as surfactants, dispersants, fillers, other polymers and oligomers, and the like, may be included within the matrix in the core. Five fifty 55 The substantially impermeable sheath prevents diffusion of the agent therethrough.

In accordance with the foregoing, the agent diffuses into surrounding body fluids, body tissues, etc. The agent's diffusion rate to the surrounding body fluids, body tissues, etc. Once a molecule of the agent reaches the exposed surface of the composition in contact with the environment, it can diffuse into the surrounding fluid or tissue.

In certain embodiments, the therapeutic agent may initially be released into a tissue structure adjacent to the target, for example to a tear point of a patient located near the target eye tissues, from where it can diffuse to the site of action.

In various embodiments, the agent may be soluble or substantially insoluble in the polymeric matrix material. In embodiments where the agent is soluble at the concentration used in the polymeric matrix material, the drug core comprises a homogeneous composition wherein the agent is dispersed at the molecular level within the polymeric matrix material. For example, a highly lipophilic agent such as ethinodiol diacetate can be dissolved at significant concentrations in a silicone polymer, such that a core can be a homogeneous dispersion of the agent in the matrix at the molecular level.

When a homogeneous dispersion of the agent is present in the matrix, the agent release rate from the exposed surface of the core to the body fluid or tissue can be controlled by the agent diffusion or transport rate through the matrix.

In embodiments where the agent is soluble in the polymer matrix material, the rate of release of the agent into the body tissue or fluid can be determined at least in part by the concentration of the agent dissolved in the core matrix.

In various embodiments, the concentration of the therapeutic agent dissolved in the matrix may be a saturation concentration. The kinetics of such release may be of zero order, first order, or a fractional order between the zero and first orders.

In embodiments where the agent is only partially or slightly soluble or insoluble in the matrix at the concentration used, the core comprises a heterogeneous composition in which the drug substance is dispersed as solid or liquid inclusions through the polymeric matrix material. When there is some solubility, however slight, a certain amount of the drug will be dissolved in the matrix.

In various embodiments, inclusions may vary in size from about 0. When inclusions of the agent are present in the matrix, the agent can be at least slightly soluble in the matrix to allow at least some diffusion of the agent from an inclusion to an exposed surface of the drug core such that the agent can diffuse subsequently to the fluid or body tissue, for example, the agent can diffuse into the tear fluid.

When the agent is insoluble in the matrix, the agent will form domains or inclusions as a separate phase within the matrix that can cooperate to allow microchannels to transport the drug to the surface of the matrix. In various embodiments, the agent can be transported through channels or pores in the matrix, which can be permeated by body fluid. In various embodiments, the agent can be transported through pores or channels present in the matrix.

The agent is present in the core, dispersed in the matrix, in a concentration. The concentration is a concentration of the agent within a macroscopic portion of the matrix-agent core, which is controlled to be similar from sample to sample of the nucleus.

A similar concentration of the agent in a macroscopic portion of the core may vary, but only within limits, with respect to any other macroscopic portion equal to the core. The term does not relate to concentrations at the molecular level, where domains or inclusions of the agent may be present in concentrated form, but instead refers to concentrations in volume of the agent in core volumes that are greater than at least about 0.

The diameter distribution of the inclusions can be monodispersed, that is, grouped relatively narrowly around the average diameter. Although not intended to be a limitation of the invention, the factors that control the release rate of the agent from the womb to the patient, such as the release of an ocular drug into the tear fluid, are considered as complex and dependent on many variables For example, a drug and a matrix material can together define a saturation concentration of the drug in that matrix.

For some drug-matrix combinations, high concentrations of the drug can dissolve in the matrix. For others, a saturation concentration is lower. For still others, there is no solubility, and separate domain phases frequently handle the release rate. Another possible factor is the rat image18 10 fifteen twenty 25 30 35 40 Four. Five fifty of mass transfer from inclusions to the surface of the matrix. Yet another possible factor is the rate of diffusion of the agent from the matrix into a body fluid, such as a tear fluid.

A therapeutic agent release rate in therapeutic amounts can be determined at least in part by a concentration of therapeutic agent in the matrix of the drug core. The therapeutic agent may be able to dissolve sufficiently in the matrix from the inclusions, if present, such that it maintains the concentration of the therapeutic agent dissolved in the matrix such that the release rat is within a therapeutic window.

This can lead to a desirable zero order release rat of the agent, since substantial agent reservoirs are present in the inclusions, while the limited solubility of the agent in the matrix is determinant of the rat by bringing the agent to the surface. In embodiments where the agent is insoluble and forms inclusions in the matrix material, the rate of release of the agent into the body tissue or fluid can be determined at least in part by the concentration of the agent as it diffuses from the inclusions to through separate domains in the matrix material to the point of exposure to tissue or body fluid.

In various embodiments, the matrix includes a material with rat release variation in an amount sufficient to release the therapeutic agent from the drug core in therapeutic amounts for an extended period when implanted for use.

The modifying material of the release rat may include an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination of the foregoing. For example, the core may include a surfactant or dispersant material, or a filler, an oligomer, another polymer, or the like, in addition to the one or more drugs and the polymeric matrix material. Examples include polymers such as polyethylene glycols PEG , sodium alginate, silicones or low molecular weight polyurethanes, etc.

Non-polymeric additives may include hydrophilic solvents such as ethylene glycol or glycerol. Depending on the drug, and the rate of drug release from the womb, the concentration can control the period of time over which therapeutic amounts of the drug are released into the body fluid, such as tear fluid.

In various embodiments, as discussed above, the nucleus may include two or more drugs. In certain embodiments, both drugs are substantially soluble in the matrix material. In other embodiments, a first drug is substantially soluble in the matrix material and a second drug forms inclusions within the matrix material.

In some embodiments, the implant comprises a core of single drugs with two therapeutic agents mixed within a matrix. In other embodiments, the implant comprises two drug cores, each with an individual therapeutic agent.

In some embodiments, the second drug may be a contractive agent to avoid a side effect of the first therapeutic agent. In one example, the first drug can be a cycloplegic drug, that is, one that blocks the accommodation focus of the eye, for example, atropine or scopolamine, and the second therapeutic agent can be at least one of an antiglaucoma drug or a miotic drug, selected to reduce the known side effect glaucoma inducer of cycloplegic drugs or to produce contraction of the pupil that counteracts the known mydriatic effects of atropine or scopolamine.

The antiglaucoma drug may comprise at least one of a sympathomimetic agent, parasympathomimetic, beta blocker, a carbonic anhydrase inhibitor, or a prostaglandin analog. In another example, the first therapeutic agent can be a steroid and the second therapeutic agent can be an antibiotic, where steroids compromise the immune response, but antibiotics provide protection against infection.

In another example, the first therapeutic agent may be pilocarpine and the second therapeutic agent may be a non-steroidal anti-inflammatory drug NSAID. An analgesic can be a good complement to treatment.

In specific embodiments, the core insert comprises an individual drug-matrix composition having two drugs contained therein. In other embodiments, the core insert comprises two separate drug matrix compositions "sub-nucleus" or first and second nuclei , arranged adjacent to each other within the sheath. The two separate compositions may be arranged in a concentric spatial configuration, in a sector configuration, or otherwise provided such that the exposed surfaces of both compositions are exposed to tissue or body fluid when disposed within the tissue, cavity or body duct of the patient.

In some embodiments the therapeutic agents may be released with a profile that corresponds to a kinetic order of release of therapeutic agents and the order may be within a range from about zero to about one. In specific embodiments, the range is from about zero to about one medium, for example from about zero to about a quarter. The therapeutic agents can be released with a profile that corresponds to a kinetic order of release of therapeutic agents and the order is within a range from about zero to about one medium for at least about a month image19 5 10 fifteen twenty 25 30 35 40 Four.

Five After the structure is inserted, for example the order may be within the range of at least about 3 months after the structure is inserted. In several embodiments, the precursor sheath can be divided by cutting with a blade or with a laser, or the like. An exposed surface of the drug core contained within the implant is capable of releasing the therapeutic amounts in at least one of the sclera, a cornea or a vitreous when they are disposed in or adjacent to the patient's eye.

For example, the implant may be a tear point plug adapted for disposition within a patient's tear point for release of the agent in the tear fluid. In various embodiments of the methods of the invention described above, the mixture may additionally comprise a solvent in which the matrix precursor and the agent are soluble, and the curing may comprise at least a partial removal of the solvent after injection into the sheath body or sheath body of the precursor respectively.

Curing may involve heating, vacuum treatment, or both. The solvent may be a hydrocarbon, an ester, a halocarbon, an alcohol, an amide, or a combination thereof.

For example, when the agent is cyclosporine, the solvent may be a halocarbon. In various embodiments, curing of the mixture may comprise heating the mixture at a temperature, at a relative humidity, for a period of time.

In various embodiments, curing may include a stage of polymerization or cross-linking, or both, of the matrix, of the matrix precursor, or both. For example, polymerization or crosslinking, or both, can be carried out in the presence of a catalyst.

For example, the catalyst can be a tin compound or a platinum compound, such as a platinum catalyst system with vinyl hydride or a tin catalyst system with alkoxy.

In various embodiments, the mixture can be prepared by a method comprising sonication. The matrix precursor and the agent can be mixed to provide a compound similar to an exhaustively dispersed emulsion, wherein the agent, if insoluble or slightly soluble in the matrix precursor, is expressed in small particles.

The mixture can be injected in such a way that the sheath body or the precursor sheath body, respectively, is filled to a rat of no more than about 0. As discussed below, Figures 15 and 16 provide graphical evidence of the advantages of extrusion to the sub-environment, both in terms of uniformity of the inclusion diameter, and in terms of uniformity of distribution of the therapeutic agent along the length of a full precursor pod. Figure 15 shows electron micrographs of cryogenic section portions of a drug core where extrusion was carried out at various temperatures.

Figure 16 graphically shows the content of latanoprost in a 10 cm precursor sheath filled with the latanoprost-silicone mixture, as discussed in examples 12 and Five silicone, after curing, along the entire length of the 10 cm precursor sheath, which was subsequently divided into 1 mm sections, and the latanoprost content of each section was determined drug inserts. In various embodiments, each drug insert can be sealed at one end thereof, thereby providing the second end with the exposed surface for agent release when the insert is disposed within an implant and inserted into a patient.

Each drug insert can be sealed at one end thereof using a UV curable adhesive, a cyanoacrylate, an epoxy, by puncturing, with heat welding, or with a cap.

When a UV curable adhesive is used, curing is carried out by irradiation with UV light. In various embodiments, the methods of the invention further comprise, after sealing one end thereof, inserting each drug insert into a channel of a respective implant body adapted to receive the insert within itself.

In various embodiments, when the drug core comprises two drug cores, the first drug core comprising a first agent and a first matrix, and a second drug core comprising a second agent and a second matrix, wherein the first agent and the second agent are different, and wherein the first matrix and the second matrix are either the same or different from each other, the implant body comprising an opening adapted to receive the drug insert comprising the first and second drug cores, the method may further comprise arranging the drug cores within the insert before disposing the insert comprising the drug cores within the opening of the implant body.

In some embodiments, the matrix comprises an inert filler material mixed with the therapeutic agent such that the exposed surface releases the therapeutic agent in therapeutic amounts for a sustained period of time.

In some embodiments, a salt is mixed with the matrix precursor such that the exposed surface of the matrix, after curing, releases the therapeutic agent in therapeutic amounts for a sustained period of time. In some embodiments, a surfactant is mixed with the matrix precursor such that the exposed surface of the matrix, after curing, releases the therapeutic agent in therapeutic amounts for a sustained period of time.

In some embodiments, a second polymer or an oligomer is mixed with the matrix precursor, and after curing to form the matrix, the presence of the second polymer or oligomer can serve to vary the rate of release of the therapeutic agent. In various embodiments, the therapeutic agent may be olopatadine, or a prodrug or a derivative of olopatadine.

For example, the agent can be olopatadine hydrochloride, also known as patanol. Used to treat allergic conjunctivitis itchy eyes , olopatadine inhibits the release of histamine from mast cells. It is a relatively selective histamine HI antagonist that inhibits the type 1 immediate hypersensitivity reaction in vivo and in vitro that includes the inhibition of histamine-induced effects in human conjunctive epithelial cells.

The cap further includes a substantially impermeable sheath, to limit the area or region of release of the therapeutic agent to the at least one exposed surface of the drug core, arranged immediately adjacent to the eye point such that the therapeutic agent easily comes into contact.

For example, cyclosporine can be released into the tear fluid to help treat the eye for dryness or inflammation, such as that caused by an allergic reaction. The sheath can also be adapted to provide a second exposed surface of the drug core located near the distal end of the cap to release the therapeutic agent into the point channel, if such a thing is desired.

For example, a second therapeutic agent, such as an antibiotic for treatment of tear canal infections, may be included. The sheath may be of sufficient elasticity or flexibility when the core is adapted to swell when it comes into contact with an aqueous medium. The swelling is adapted to aid in retaining the plug within the tear canal. Five fifty E The core may additionally contain a second bioactive agent, as listed below, such as for the treatment of a secondary condition or to aid in the treatment of the condition, for example, for which the administration of cyclosporine or olopatadine, or Both are medically indicated.

The tear implant can be of any suitable shape adapted for insertion in the eye canal. For example, the implant may be substantially cylindrical at the time of insertion into the canal, before swelling of any hydrogel-forming core of the plug.

Or, the implant may be conical in shape, or it may be folded in the form of an "L", or it may have any other shape that may be arranged within the point channel of an eye of a patient such that the agent Therapeutic can be released from the nucleus into the tear fluid by bathing the eye. According to the above, the implant core, when the implant is disposed within the tear point channel, has access to the point opening so that the agent can diffuse into the tear fluid and therefore bathe the surface of the eye.

In various embodiments, the core has access to the inside of the tear point channel for agent release to it. For example, the implant may be in a form called "folded design" as discussed in a patent application filed concurrently with this application.

Or, the implant may be of a design referred to as the "H design", as disclosed in a patent application filed concurrently with this application. Or, the implant may be what is called the "skeleton" design as disclosed in a patent application filed concurrently with this application. Thus, the fusion mixing processes can be fusion to form an implant of the invention. For example, the mixed melt may be melted in a mold already coated with a higher melting point sheath material. In this way the sheathed implant can be prepared.

Alternatively, the core can be cast in a mold, then the wrapping material can be placed as a coating or cast on the surface of the implant, except for regions where the core material should be left exposed.

Or, the sheath material may be molten to cover the entire implant, and then a portion removed to expose the core material at least one location near the proximal end, where the cyclosporine can easily come into contact with the tear fluid and therefore spread to the eye.

The implant of the invention can be used to treat a condition of the eye or surrounding tissue. For example, the implant that incorporates cyclosporine or olopatadine, or both, can be used to treat an eye condition that involves dry eye or inflammation of the eye.

The therapeutic agent can be released into the eye, as well as the surrounding tissue such as inside the tear canal, for a period of time. The period of time can be from about 1 week to about 6 months.

The disclosure provides a method of treating a condition in a patient that so requires, which comprises arranging an implant comprising a drug insert of the disclosure, or a drug core of the disclosure, or a drug core obtained by division of a precursor sheath filled with the disclosure, or a drug implant of the disclosure, or a drug insert prepared by the method of the invention, wherein the therapeutic agent is adapted to treat the condition, in or adjacent to an eye of the patient such that the drug is released into a tissue or body fluid.

The disclosure provides the use of a drug insert of the disclosure, or of a drug core of the disclosure, or of a drug core obtained by dividing a precursor sheath filled with the disclosure, or a drug implant of the disclosure, or a drug insert prepared by the method of the invention, in the manufacture of an implant adapted for treatment of a condition in a patient that so requires.

The disclosure provides a drug insert adapted for disposal within a tear point cap to provide sustained release of a latanoprost to the eye for treatment of glaucoma, the insert comprising a core and a sheath body that partially covers the core, the core comprising the latanoprost and a matrix wherein the matrix comprises a silicone polymer, the latanoprost being dispersed within the silicone as droplets thereof, wherein an amount of latanoprost in a volumetric portion of the drug core is similar to an amount of latanoprost in any other equal volumetric portion of the drug core, the sheath body being disposed on a portion of the core to inhibit the release of latanoprost from said portion, an exposed core surface not covered by the sheath body being adapted to release the sheath Latanoprost towards the eye.

Discussion of the figures Figure 1A shows a top cross-sectional view of a sustained-release implant for treating an optical defect of an eye. The implant includes a drug core The drug core is an implantable structure that retains the therapeutic agent. The drug core comprises a matrix containing inclusions of the therapeutic agent. The inclusions will frequently comprise a concentrated form of the therapeutic agent, for example, a crystalline form of the therapeutic agent, and the therapeutic agent may eventually dissolve.

Five fifty 55 in matrix of drug core The matrix may comprise a silicone matrix or the like, and the mixture of the therapeutic agent within the matrix may be non-homogeneous.

In many embodiments, the non-homogeneous mixture comprises a portion of silicone matrix that is saturated with the therapeutic agent and a portion of inclusions comprising inclusions of the therapeutic agent, such that the non-homogeneous mixture comprises a non-homogeneous multiphase mixture. In some embodiments, inclusions comprise droplets of an oil of the therapeutic agent, for example latanoprost oil. In some embodiments, inclusions may comprise particles of the therapeutic agent, for example, solid bimatoprost particles in crystalline form.

The encapsulated inclusions dissolve in the surrounding solid matrix, for example silicone, which encapsulates the microparticles such that matrix is substantially saturated with the therapeutic agent while the therapeutic agent is released from the nucleus. The drug core is surrounded by a sheath body The sheath body may be substantially impermeable to the therapeutic agent, such that the therapeutic agent is frequently released from an exposed surface or from a drug core end that is not covered with a sheath body A retention structure is connected to a drug core and a sheath body The retention structure is configured to retain the implant in a hollow tissue structure, for example, a tear point of a canaliculus as described above.

An occlusion element is disposed on and around the retention structure The occlusion element is impervious to the flow of tears and occludes the hollow tissue structure and can also serve to protect the tissues of the tissue structure from the retention structure by providing a more benign tissue engagement surface.

The sheath body includes a sheath body portion that connects to the retention structure to retain the sheath body and the drug core The sheath body portion may include a retainer to limit movement of the sheath body and the drug core In many embodiments, the sheath body portion may be shaped with a bulbous tip B. The bulbous tip B may comprise a convex rounded outer portion that provides an atraumatic entry to the introduction into the canaliculus.

In many embodiments, the sheath body portion B may be integral with the occlusion element Figure 1B shows a side cross-sectional view of the sustained release implant of Figure 1A. The drug core is cylindrical and shows a circular cross section. The sheath body comprises an annular portion disposed in a drug core The retention structure comprises several longitudinal uprights The longitudinal uprights are connected to each other near the ends of the retention structure.

Although longitudinal struts are shown, circumferential struts can also be used. The occlusion element is supported by and disposed on longitudinal uprights of retention structure and may comprise a radially expandable membrane or the like.

Figure 1C shows a perspective view of a sustained release implant with a spiral retention structure The retention structure comprises a spiral and retains a drug core A lumen, for example channel C, can be extended through the drug core to allow tear flow through the lumen for administration of the therapeutic agent for nasal and systemic applications of the therapeutic agent.

The drug core may be partially covered. The sheath body comprises a first component A that covers a first end of the drug core and a second component B that covers a second end of the drug core. Figure 1D shows a perspective view of the sustained release implant with a retention structure comprising uprights.

The retention structure comprises longitudinal uprights and retains a drug core The drug core is covered with a sheath body over most of the drug core The drug core releases the therapeutic agent through an exposed end and the sheath body is annular over most of the drug core as described above.

An occlusion element may be placed on the retention structure or the retention structure may be coated by immersion as described above. A protrusion that can be hooked with an instrument, for example a hook, a loop, a suture or a ring R, can be extended from the sheath body to allow removal of the drug core and sheath body together in such a manner. In some embodiments, a protrusion that can be engaged with an instrument comprising a hook, a loop, a suture or a ring, can extend from the retention structure to allow removal of the sustained release implant by eliminating the retention structure with the protrusion, the drug core and the sheath body.

Five fifty 55 Figure 1E shows a perspective view of a sustained release implant with a cage retention structure The retention structure comprises several connected metal wires and retains a drug core Figure 1F shows a perspective view of a sustained release implant comprising a core and a sheath.

The therapeutic agent release rate is controlled by the surface area of the exposed drug core and the materials included within the drug core In many embodiments, the dilution rate of the therapeutic agent is strongly and substantially related to the surface area of the drug core and is weakly dependent on the concentration of drug arranged in inclusions in the drug core.

For exposed circular surfaces the dilution rate depends strongly on the diameter of the exposed surface, for example the diameter of a drug core surface exposed near one end of a cylindrical drug core. Such an implant can be implanted in ocular tissues, for example below the layer 9 of connective tissue of the eye and either above the layer 8 of sclerotic tissue, as shown in Figure 1F, or only partially within the layer.

It should be noted that the drug core can be used with any of the retention structures and occlusion elements as described herein. In one embodiment, the drug core is implanted between the sclera 8 and the conjunctiva 9 without the sheath body In this embodiment without the sheath body, the physical characteristics of the drug core can be adjusted to compensate for the increased exposed surface area of the drug core, for example, by reducing the concentration of the therapeutic agent dissolved in the drug core matrix as described.

Figure 1G schematically illustrates a sustained release implant comprising a flow restriction retention structure , a core and a sheath The sheath body can at least partially cover the drug core The drug core may contain inclusions of the therapeutic agent itself to provide a sustained release of the therapeutic agent. Drug core may include an exposed convex surface area A.

The exposed convex surface area A may provide an increased surface area to release the therapeutic agent. An occlusion element may be arranged on the retention structure to block tear flow through the canaliculus. In many embodiments, the retention structure may be located within the occlusion structure to provide the occlusion element integrated with the retention structure. The retention structure for flow restriction and the occlusion element can be sized to block tear flow through the canaliculus.

The nuclei and sheath bodies described herein can be implanted in a variety of tissues in various ways. Many of the cores and sheaths described herein, in particular the structures described with reference to Figures 2A to 2J, can be implanted alone as tear point plugs. Figure 2A shows a cross-sectional view of a core-sustained implant comprising an enlarged exposed surface area. A drug core is covered with a sheath body The sheath body includes an opening A.

The opening has a diameter that approximates the diameter of the maximum cross section of the drug core The drug core includes an exposed surface E, also referred to as an active surface. The exposed surface E includes 3 surfaces: an annular surface A, a cylindrical surface B, and an end surface C. The annular surface A has an external diameter that approximates the maximum cross-sectional diameter of the core and an internal diameter that approximates the external diameter of the cylindrical surface B.

The end surface C has a diameter that matches the diameter of the cylindrical surface B. The surface area of the exposed surface E is the sum of the areas of the annular surface A, the cylindrical surface B and the end surface C. The surface area may be increased by the size of the cylindrical surface area B that extends longitudinally along a core axis Figure 2B shows a cross-sectional view of a sustained release implant with a core comprising an enlarged exposed surface area A.

A sheath body extends over the core The treatment agent can be released from the core as described above. The exposed surface area A is approximately conical, may be ellipsoidal or spherical, and extends outwardly from the sheath body to increase the exposed surface area of the drug core Five fifty 55 Figures 2C and 2D show perspective and cross-sectional views, respectively, of a sustained-release implant with a drug core comprising a reduced exposed surface area A.

The drug core is included within a sheath body. The sheath body 22 includes an annular end portion A defining an opening through which the drug core extends. The drug core includes an exposed surface surface A that releases the therapeutic agent.

The exposed surface A has a diameter D that is smaller than a maximum dimension, for example a maximum diameter, through the drug core Figure 2E shows a cross-sectional view of a sustained-release implant with a drug core comprising an enlarged exposed surface area A with crenellated extending therefrom.

The casing includes several fingers F separated from each other to provide increased surface area of the exposed surface A.

In addition to the increased surface area provided by the crenellated, the drug core may also include an indentation The indentation may take the form of an inverted cone. The core is covered with a sheath body The sheath body is open at one end to provide an exposed surface A on the drug core The sheath body also includes fingers and has a crenellated pattern that matches core Figure 2F shows a perspective view of a sustained release implant comprising a core with folds.

The implant includes a core and a sheath body The core has a surface A exposed on the end of the core which allows the drug to migrate to the tear fluid or to the surrounding tear film. Core also includes F folds. The F folds increase the surface area of the core that is exposed to the surrounding tear fluid or tear film fluid.

With this increase in the exposed surface area, the F folds increase the migration of the therapeutic agent from the core to the tear or tear film fluid and the target treatment area. The folds F are formed in such a way that a channel C is formed in the core The channel C connects to the end of the core to an opening in the exposed surface A and provides the migration of the treatment agent. Thus, the total exposed surface area of the core includes the exposed surface A that is directly exposed to the tear or tear film fluid and to the surface of the folds F that are exposed to the tear or tear film fluids through the connection of channel C with surface A exposed and to tear or tear film fluid.

Figure 2G shows a perspective view of a sustained release implant with a core comprising a channel with an internal surface. The core has a surface A exposed on the end of the core that allows the drug to migrate to the tear fluid or surrounding tear film. The core also includes a channel C. Channel C increases the surface area of the channel with an internal surface P formed on the inside of the channel against the core. In some embodiment, the internal exposed surface may also be porous.

Channel C extends toward the end of the core near the exposed surface A of the core. The surface area of the core that is exposed to the surrounding tear or tear film fluid may include the inside of the core that is exposed to the channel C.

This increase in the exposed surface area may increase the migration of the therapeutic agent from the core to the tear or tear film fluid and to the target treatment area. Thus, the total exposed surface area of the core may include the exposed surface A that is directly exposed to the tear or tear film fluid and to the internal surface P that is exposed to the tear or tear film fluids through the connection of the channel C with the exposed surface A and the tear or tear film fluid.

Figure 2H shows a perspective view of a sustained release implant with a core comprising channels for increasing drug migration. The exposed surface A is located on the end of the core , although the exposed surface may be positioned in other locations. The exposed surface A allows the migration of the drug to the surrounding tear or tear film fluid. The core also includes channels C. Channels C extend to exposed surface The channels C are large enough so that the tear fluid or tear film can enter the channels and therefore increase the surface area of the core that is in contact with the tear or tear film fluid.

The surface area of the core that is exposed to the surrounding tear or tear film fluid includes the inner surface P of the core defining the channels C. With this increase in the exposed surface area, the channels C increase the migration of the therapeutic agent from the nucleus to the tear fluid or tear film and to the target treatment area. Thus, the total exposed surface area of the core includes the exposed surface A that is directly exposed to the tear or tear film fluid and the internal surface P that is exposed to the tear or tear film fluids through the connection of the C channels with exposed surface A and tear or tear film fluid.

Figure 21 shows a perspective view of the sustained release implant with a drug core comprising an exposed convex surface A. The drug core is partially covered with a body image24 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 of sheath that extends at least partially over the drug core to define the exposed convex surface A.

The sheath body comprises a shaft portion S. The exposed convex surface A provides an increased exposed surface area above the sheath body. A cross-sectional area of the exposed convex surface A is larger than a cross-sectional area of the shaft portion S of the sheath body In addition to the larger cross-sectional area, exposed convex surface A has a larger surface area due to the convex shape which extends outwardly from the core.

The sheath body comprises several fingers F that support the drug core in the sheath body and provide support to the drug core to hold the drug core in place in the sheath body The fingers F are separated from each other to allow migration of the drug from the core to the tear fluid or tear film between the fingers.

The protrusions P extend outwardly over the sheath body The protrusions P can be pressed inward to produce ejection of the drug core from the sheath body The drug core may be replaced with another drug core after an appropriate time, for example after the drug core has released most of the therapeutic agent. Figure 2J shows a side view of the sustained-release implant with a core comprising an exposed surface area with several members F similar to soft bristles.

The drug core is partially covered with a sheath body that extends at least partially over the drug core to define the exposed surface A. The soft bristle-like members F extend outwardly from the drug core and provide an increased exposed surface area to the drug core The F members similar to soft bristles are also soft and resilient and easily undergo deflection such that these members do not cause irritation to the surrounding tissue.

Although the drug core can be made of many materials as explained above, silicone is a suitable material for the manufacture of a drug core which also comprises F members similar to soft bristles. The exposed surface A of the drug core also includes an indentation such that at least a portion of the exposed surface A is concave. Figure 2K shows a side view of a sustained release implant with a drug core comprising an exposed convex surface A. The drug core is partially covered with a sheath body that extends at least partially over the drug core to define the exposed convex surface A.

Convex exposed surface provides an exposed surface area increased above the sheath body. A cross-sectional area of the exposed convex surface A is larger than a cross-sectional area of a shaft portion S of the sheath body In addition to the cross-sectional area, the exposed convex surface A has a larger surface area due to the convex shape extending outwardly over the core. The retention structure can be attached to the sheath body The retention structure may be coated by immersion to make the retention structure biocompatible.

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