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WO2009032266A2 - Dispersions de microparticules et de microgels dans des hydrogels pour la libération de médicaments - Google Patents

Dispersions de microparticules et de microgels dans des hydrogels pour la libération de médicaments Download PDF

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Publication number
WO2009032266A2
WO2009032266A2 PCT/US2008/010352 US2008010352W WO2009032266A2 WO 2009032266 A2 WO2009032266 A2 WO 2009032266A2 US 2008010352 W US2008010352 W US 2008010352W WO 2009032266 A2 WO2009032266 A2 WO 2009032266A2
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WIPO (PCT)
Prior art keywords
bioactive agent
drug
delivery system
contact lens
ophthalmically
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PCT/US2008/010352
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English (en)
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WO2009032266A3 (fr
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Anuj Chauhan
Chi-Chung Li
Hyun-Jung Jung
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University Of Florida
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Publication of WO2009032266A2 publication Critical patent/WO2009032266A2/fr
Publication of WO2009032266A3 publication Critical patent/WO2009032266A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • G—PHYSICS
    • G02—OPTICS
    • G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
    • G02C7/00—Optical parts
    • G02C7/02—Lenses; Lens systems ; Methods of designing lenses
    • G02C7/04—Contact lenses for the eyes

Definitions

  • TITLE DISPERSIONS OF MICROP ARTICLES AND MICROGELS IN HYDROGELS FOR DRUG DELIVERY
  • the present invention relates to methods and systems for the delivery of drugs to patients in need thereof. Specifically, the present invention relates to ophthalmically bioactive agent delivery system.
  • Topical delivery via eye drops that accounts for about 90% of all ophthalmic formulations is very inefficient and in some instances leads to serious side effects [Lang, J. C, "Ocular drug delivery conventional ocular formulations”. Adv. Drug Delivery, 1995, 16: 39- 43]. Only about 5% of the drug applied as drops penetrate through the cornea and reaches the ocular tissue, while the rest is lost due to tear drainage [Bourlais, C.L., Acar, L., Zia H., Sado, P.A., Needham, T., Leverge, R., “Ophthalmic drug delivery systems", Progress in retinal and eye research, 1998, 17, 1 : 33-58].
  • the drug mixes with the fluid present in the tear film upon instillation and has a short residence time of about 2-5 minutes in the film. About 5% of the drug gets absorbed and the remaining flows through the upper and the lower canaliculi into the lacrimal sac.
  • the drug containing tear fluid is carried from the lacrimal sac into the nasolacrimal duct, and eventually, the drug gets absorbed into the bloodstream. This absorption leads to drug wastage and more importantly, the presence of certain drugs in the bloodstream leads to undesirable side effects.
  • beta-blockers such as Timolol that is used in the treatment of wide-angle glaucoma have a deleterious effect on heart [TIMPOTIC prescribing information, supplied by MERCK].
  • Graziacascone et al discloses a study on encapsulating lipophilic drugs inside nanoparticles, and entrapping the particles in hydrogels.
  • Graziacascone, M., Zhu, Z., Borselli, F., Lazzeri, L., "Polyvinyl alcohol) hydrogels as hydrophilic matrices for the release of lipophilic drugs loaded in PLGA nanoparticles Journal of Material Science: Materials in Medicine, 2002, 13: 29-32.
  • PVA hydrogels as hydrophilic matrices for the release of lipophilic drugs loaded in PLGA particles.
  • a bioactive agent delivery system comprising a substantially optically transparent contact lens having dispersed therein (1) an ophthalmically bioactive agent, the agent being capable of diffusion through the contact lens and into the post-lens tear film when the contact lens is placed on the eye and (2) associated with the bioactive agent, at least one ophthalmically compatible polymeric surfactant, the polymeric surfactant being capable of forming a microemulsion and being present in an amount sufficient to attenuate the rate of migration of the bioactive agent through the contact lens.
  • the invention comprises trapping drug-loaded highly crosslinked EGDMA microparticles and microgels into contact lenses.
  • a number of researchers have developed microgels and microparticles of various types and utilized these for drug delivery applications.
  • an ophthalmically bioactive agent delivery system comprising a contact lens having dispersed therein microparticles or microgels of a crosslinked polymer, said microparticles or microgels having entrapped therein an ophthalmically bioactive agent, said crosslinked polymer comprising an ophthalmically acceptable material from which said bioactive agent is capable of diffusion into and migration through said contact lens and into the post-lens tear film when said contact lens is placed on the eye and wherein the degree of polymerization and/or crosslinking is such that the rate of diffusion into and migration through said contact lens of said ophthalmically bioactive agent is attenuated.
  • ophthalmically acceptable is meant that a material has substantially no detrimental effect on the mammalian eye into which it is placed.
  • a second embodiment of the invention is a method of administering a bioactive agent to a patient in need thereof comprising placing on the eye the above described drug delivery system.
  • kits and its use for the storage and delivery of ophthalmic drugs to the eye comprising: a) a first component containing at least one of the above described drug delivery systems, and b) a second component containing at least one storage container for the first component, the storage container additionally containing a material that substantially prevents the diffusion and migration of the ophthalmic drug during storage.
  • a fifth embodiment of the invention relates to a method of manufacturing a bioactive agent delivery system comprising providing a monomer mixture having a lens- forming monomer, the microparticles or microparticles loaded with the bioactive agent and polymerizing said monomer mixture.
  • Sixth and seventh embodiments of the invention concern articles of manufacture comprising packaging material and the above described drug delivery system or the above- described kit contained within the packaging material, wherein the packaging material comprises a label which indicates that the drug delivery system and kit can be used for ameliorating symptoms associated with pathologic conditions of the eye
  • Figure 1 illustrates Timolol base form release from PHEMA gel directly entrapped with Timolol base.
  • Figure 2(a) illustrates release from IX microparticle-laden gels loading gels (200 micron thick, EGDMA particles). The gel weighed 0.0476g.
  • Figure 2(b) illustrates release from 2X microparticle-laden gels loading gels (100 micron thick, EGDMA particles). The gel weighed 0.0246g.
  • Figure 2(c) illustrates release from 4X microparticle-laden gels loading gels (100 and 200 micron thick, PGT particles). Gel weights are 0.0230 and 0.0504 g for the 100 and 200 ⁇ m thick gels.
  • Figure 2(d) illustrates release from 7X microparticle-laden gels loading gels (100 and 200 micron thick, PGT particles). Gel weights are 0.0239 and 0.0515 g for the 100 and 200 ⁇ m thick gels.
  • Figure 2(e) illustrates release from 4X microparticle-laden gels loading gels (100 and 200 micron thick, ETT particles). Gel weights are 0.0250 and 0.0556 g for the 100 and 200 ⁇ m thick gels.
  • Figure 2(f) illustrates release from 7X microparticle-laden gels loading gels (100 and 200 micron thick, ETT particles). Gel weights are 0.0269 and 0.0569 g for the 100 and 200 ⁇ m thick gels.
  • Figure 2(g) illustrates release from 2X microparticle-laden gels loading gels (100 and 200 micron thick, EGDMA particles). Gel weights are 0.0246 and 0.0573 g for the 100 and 200 ⁇ m thick gels.
  • Figure 3 (a) illustrates release from 4X Timolol loading gels (100 and 200 micron, PGT crosslinker) in 100 ppm solution (timolol/PBS).
  • the gel weights are 0.0267 and 0.0537 g for the 100 and 200 micron thick gels.
  • Figure 3(b) illustrates uptake by 4X Timolol loading gels (100 and 200 micron, PGT crosslinker) in 1000 ppm solution (timolol/PBS). The gel weights are 0.0364 and 0.0535 g for the 100 and 200 micron thick gels.
  • Figure 3(c) illustrates uptake by 4X Timolol loading gels (100 and 200 micron, PGT crosslinker) in 2500 ppm solution (timolol/PBS). The gel weights are 0.0311 and 0.0584 g for the 100 and 200 micron thick gels.
  • Figure 3(d) illustrates release of timolol into 3.5 ml PBS after packaging in 1 ml PBS for 1 month for 200 micron thick 2X(lower curve) and 4X (upper curve) EGDMA gels.
  • Gel weights are 0.0597 and 0.0601 g for the 100 and 200 ⁇ m thick gels.
  • Figure 3(e) illustrates release of timolol into 3.5 ml PBS after packaging in 1 ml PBS for 1 month for 100 micron thick 4X EGDMA gels. The gel weighed 0.0263g.
  • Figure 4 illustrates Timolol release from microgelA-laden PHEMA gel.
  • the top three curves correspond to incomplete mixing during extraction data and the bottom two correspond to perfect mixing.
  • the numbers on the curves represent the fraction of loaded drug that was released during the initial extraction.
  • Figure 5 illustrates Timolol released from PHEMA lenses loaded with microgels B, C, and D. Extraction was conducted under perfect mixing conditions for each gel. The numbers on the curves represent the fraction of loaded drug that was released during the initial extraction.
  • the present invention is predicated on the discovery that contact lenses, preferably, soft contact lenses can function as new vehicles for ophthalmic drug delivery to reduce drug loss, eliminate systemic side effects, and improve drug efficacy.
  • the contact lenses of the present invention are formed from reaction mixtures which comprise the reactive components, catalyst, other desired components, and optionally a solvent.
  • the reaction mixtures may be cured using conventionally known conditions, known to those skilled in the art.
  • Hydrophilic components are those which when mixed, at 25°C in a 1 :1 ratio by volume with neutral, buffered water (pH about 7.0) forms a homogenous solution. Any of the hydrophilic monomers known to be useful to make hydrogels may be used.
  • the hydrophilic monomer comprises at least one of DMA,
  • HEMA glycerol methacrylate, 2-hydroxyethyl methacrylamide, NVP, N-vinyl-N-methyl acrylamide, N-methyl-N-vinylacetamide, polyethyleneglycol monomethacrylate, methacrylic acid and acrylic acid, polymers and copolymers of any of the foregoing, mixtures thereof.
  • reaction mixtures may also comprise at least one hydrophobic component.
  • Hydrophobic components are those which when mixed, at 25°C in a 1:1 ratio by volume with neutral, buffered water (pH about 7.0) form an immiscible mixture.
  • suitable hydrophobic components include silicone containing components, fluorine containing components, components comprising aliphatic hydrocarbon groups having at least 3 carbons, combinations thereof and the like.
  • the term component includes monomers, macromers and prepolymers.
  • “Monomer” refers to lower molecular weight compounds that can be polymerized to higher molecular weight compounds, polymers, macromers, or prepolymers.
  • the term “macromer” as used herein refers to a high molecular weight polymerizable compound. Prepolymers are partially polymerized monomers or monomers which are capable of further polymerization.
  • the p-HEMA hydrogel matrix may be synthesized by any convenient method, e.g., bulk or solution free radical polymerization of HEMA monomers in presence of a cross linker such as ethylene glycol-di-methacrylate (EGDMA) [Mandell, R.B., "Contact Lens Practice: Hard and Flexible Lenses", 2 nd ed., Charles C. Thomas, Springfield, vol. 3, 1974]. [0045] Addition of the drug-laden highly crosslinked microparticles and/or microgels to the polymerizing medium and subsequent polymerization results in the formation of a dispersion of the microgels and/or microparticles in the hydrogel matrix.
  • a cross linker such as ethylene glycol-di-methacrylate (EGDMA)
  • EGDMA ethylene glycol-di-methacrylate
  • POLTF post-lens tear film
  • the drug molecules will diffuse from the particles, travel through the lens matrix, and enter the post-lens tear film (POLTF), i.e., the thin tear film trapped in between the cornea and the lens, hi the presence of the lens, drug molecules will have a much longer residence time in the post-lens tear film, compared to about 2-5 minutes in the case of topical application as drops [Bourlais, C. L., Acar, L., Zia H., Sado, P.A., Needham, T., Leverge, R., "Ophthalmic drug delivery systems ", Progress in retinal and eye research, 1998, 17, 1 : 33-58; Creech, J.
  • drug-laden contact lenses can provide continuous drug release for extended periods of time.
  • the mechanism of attenuation of migration of the active agent is a slowing of migration of the active agent from the microparticles and microgels by the degree of polymerization and/or crosslinking of the material in which the bioactive agent is entrapped.
  • Suitable crosslinking agents include, e.g., (bis-acrylylcystamine), piperazine di- acrylamide), triallyl citric triamide, ethylene diacrylate, N,N'-methylenebisacrylamide, N 5 N'-
  • Example 1 Synthesis of HEMA gels loaded with highly crosslinked micro-particles.
  • ETT ethoxylated trimethylol propane triacrylate
  • the first step in the synthesis of gels loaded with highly crosslinked microparticles requires the synthesis of an emulsion of the monomer (EGDMA, PGT or ETT) in water. These monomers are hydrophobic, and so these form the oil phase in the emulsion. Hydrophobic drugs such as cyclosporine, dexamethasone, or the base form of timolol can be dissolved in the monomer drops. The drug containing drops are then polymerized to yield the drug loaded crosslinked EGDMA microparticles. Since these monomers contains multiple vinyl groups, the particles are highly crosslinked. Also drug (ex.
  • Timolol base is added to the emulsion particles to obtain 'templated or imprinted' particles, i.e., these particles have a high partitioning for the drug because of creation of pockets in the particles that recognize the drug molecules.
  • the details of the process are as follows: 6 g of 1.04M NaOH (purged with nitrogen) were added to 120 mg of timolol maleate powder. At such a high pH, timolol maleate forms the base form of timolol that is relatively hydrophobic. To concentrate the base form, 5 ml of the upper water phase was pipetted out.
  • the drug laden micro-particles (EGDMA, PGT or ETT) were loaded in p- HEMA hydrogels by adding the concentrated particle dispersion to the HEMA monomer mix followed by polymerization. Specifically, 1.35 ml of the HEMA monomer, 0.5 ml DI water, 5 ⁇ l of ethylene glycol dimethacrylate (EGDMA), and 0.1 g of the concentrated particle suspension were mixed together in a glass tube. This solution was degassed by bubbling nitrogen for 15 minutes to reduce the amount of dissolved oxygen. Next, 3 mg of the photoinitiator, Darocur TPO, was added to the mixture, and the solution was stirred for 15 minutes.
  • ETDMA ethylene glycol dimethacrylate
  • the mixture was then poured in between two glass plates separated by a 100 or 200 ⁇ m thick plastic spacer.
  • the glass plates were then placed on a UV-light illuminator (UVB) for 40 minutes for gel curing.
  • UVB UV-light illuminator
  • the gels prepared with the procedure described above are referred as IX gels.
  • the amount of particle suspension was doubled and quadrupled to obtain 2X and 4X gels, respectively.
  • For PGT, 7X gels were also prepared.
  • Control pHEMA gels were prepared by following the same procedure as described above for preparing microparticle-laden gels except that the microparticle suspension was not added. Timolol was loaded into the gels by directly adding it to the polymerizing mixture. Subsequently the drug containing pHEMA gel was cut into circular pieces with 1.65 cm diameter and 0.2 mm thickness, dried out in the air overnight, and then weighed the next day before the drug release experiment. Next the gel was soaked in 3.5 PBS and dynamic drug concentration in PBS was measured to determine the amount of drug released from the gel. The drug release profiles for these control p-HEMA gels are shown in Fig. 1 (Timolol base form release from PHEMA gel directly entrapped with Timolol base). The data clearly shows that 200 ⁇ m thick pHEMA gels release drug for a short period of about 4 hours and so are not useful for extended delivery.
  • Example 3 Timolol release from p-HEMA lenses loaded with highly crosslinked EGDMA microparticles
  • the time-dependent concentrations of timolol in PBS were determined by measuring the absorbance as a function of time by UV- Vis spectrophotometer in the 261-309nm wavelength range.
  • the timolol concentrations were also measured by a HPLC using a reverse phase Cl 8 column (Symmetry** Cl 8, Waters).
  • the samples were measured with a flow rate of 1 ml/min of the mobile phase at 30 0 C, and detected at 280nm.
  • Figures 2a-g show drug release profiles from microparticle-laden gels for several different types of particles (EGDMA, PGT or ETT), for several different crosslinker loadings (IX, 2X, 4X, 7X), and for two different thicknesses (100 and 200 microns).
  • the weights of the gels used in the release studies were slightly different for different cases and are indicated in the figure captions.
  • the data in Figs. 2 clearly show that there is an extended drug release from the gel which lasts for about 10-15 days. This release duration is substantially longer than the duration of release from the control pHEMA gels, and the duration of release is relatively independent of the gel thickness proving that the extended release is occurring due to drug trapped inside the particles.
  • Example 4 Packaging of microparticle-laden gels
  • a typical contact lens first undergoes an extraction and is then stored in packaging solution for an extended period of time. Drug molecules could potentially diffuse out of the particles into the gel and/or packaging solution during storage. It was thus decided to package the gels in drug solutions to determine if drug molecules can be prevented from being released from the particles by packaging in solutions with adequate drug concentrations.
  • These experiments were conducted with protocols same as the drug release experiments described in Example 2 except that drug solutions in PBS were used as the mediums rather than PBS.
  • the amount of drug in the solution is plotted as a function of time in Figures 3 a-c. The initial drop in the drug amount is due to rapid drug uptake into the gel. The slow reduction later is due to drug partitioning into the microparticles.
  • Example 5 Synthesis of HEMA gels loaded with highly crosslinked EGDMA microgels [0058] It is well known that free radical polymerization leads to formation of micron sized gels at short times, and these subsequently grow larger, and eventually depending on the water fraction, join to form one contiguous gel. If the polymerization is terminated at short times by quenching, one may obtain a dispersion of micro gels in the continuous phase which could be monomer and linear or weakly crosslinked polymer (bulk polymerization) or a mix of the monomer and linear or weakly crosslinked polymer in the solvent (solution polymerization).
  • EGDMA microgels a process for the formation of EGDMA microgels, and the subsequent entrapment of these micro gels in HEMA gels to yield a HEMA gel that contains small but highly crosslinked EGDMA microgels. Since EGDMA monomer contains 2 vinyl groups, the micro gels of EGDMA become highly crosslinked. The degree of crosslinking can be reduced by incorporating some fraction of HEMA into the micro gels. [0059] To synthesize micro-gels of pure EGDMA, first, timolol base was generated by adding 6 g of 1.04M NaOH to 240 mg of timolol maleate. Next 11 ml of the upper water phase was pipetted out to increase the fraction of the timolol base in the mixture.
  • timolol base was extracted with 0.85 g of benzoyl peroxide/EGDMA mixture (2.9:97.1 ratio by weight).
  • the solution was heated at 80°C for 15 minutes, followed by quenching in a 0°C water bath.
  • the solution at this stage is a dispersion of EGDMA microgels in monomelic EGDMA with some linear polymeric or weakly crosslinked chains.
  • 7.2 ml of un-purged DI water was added to the solution to completely stop the reaction.
  • the solution with microgels was then stirred at 600 rpm for 12 minutes, vortexed for 30 seconds, and then left stationary on the counter over night.
  • microgel solution replaced the particle suspension.
  • HEMA monomer 5 ⁇ l of ethylene glycol dimethacrylate (EGDMA)
  • EGDMA ethylene glycol dimethacrylate
  • 1 g of the micro gel solution were mixed together in a glass tube. This solution was degassed by bubbling nitrogen for 15 minutes to reduce the amount of dissolved oxygen which can be a scavenger of both initiating and propagating species in radical polymerization.
  • 3 mg of the photoinitiator, Darocur TPO was added to the mixture, and the solution was stirred for 15 minutes.
  • the mixture was then poured in between two glass plates separated by a 100 or 200 ⁇ m thick plastic spacer. The glass plates were then placed on a UV-light illuminator (UVB) for 40 minutes for gel curing.
  • UVB UV-light illuminator
  • the drug release experiments reported below were performed by soaking the gel sample in 3.5 PBS, and measuring concentration every 24 hours without replacing the PBS.
  • the time-dependent concentrations of timolol in PBS were determined by measuring the absorbance as a function, of time by UV- Vis spectrophotometer in the 261-309 nm wavelength range.
  • the timolol concentrations were also measured by a HPLC using a reverse phase Cl 8 column.
  • the samples were measured with a flow rate of 1 ml/min of the mobile phase at 30°C, and detected at 280nm.
  • Fig. 4 The drug release results for hydrogel loaded with bulk polymerized EGDMA micro- gels A are shown in Fig. 4 (Timolol release from microgelA-laden PHEMA gel).
  • the four curves correspond to four gels that were prepared identically but had different extent of mixing in the extraction stage.
  • These systems also exhibit an initial burst because of incomplete drug removal during the extraction phase followed by a slow release for a period of about 10 days.
  • the total drug release from these systems is about 20 ⁇ g in 10 days, and if the initial burst is excluded the released amount is about 1 ⁇ g/day.
  • the total drug release from these systems are about 110, 50, and 30 ⁇ g in 10 days, and if the initial bursts are excluded, the release rates are about 2, 1, and 4.5 ⁇ g/day for microgel B, C, and D, respectively.
  • the results suggest that the longer polymerization time applied for the synthesis of microgels, the slower the release of timolol out of these microgels. This makes sense because the larger the highly crosslinked domains, the longer it takes for drug to diffuse out of these domains.
  • the present invention is also applicable for the incorporation in hydrophobic lenses such as, for example, silicone, polydimethylsiloxane, TRIS, methyl methacrylate, tris(trimethylsiloxysilyl)propyl (meth)acrylate, triphenyldimethyl- disiloxanylmethyl (meth)acrylate, pentamethyl-disiloxanylmethyl (meth)acrylate, tert-butyl- tetramethyl- disiloxanylethyl (meth)acrylate, methyldi(trimethylsiloxy)silylpropyl-glyceryl (meth)acrylate; pentamethyldi-siloxanyl-methyl methacrylate; heptamethylcyclotetrasiloxy methyl methacrylate; heptamethylcyclotetrasiloxy-propyl methacrylate; (trimethylsilyl)- decamethyl-pentasiloxy-propyl methacrylate

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Abstract

L'invention concerne un système de libération d'agent ophtalmiquement bioactif, qui comprend une lentille de contact dans laquelle sont dispersés des microparticules ou des microgels d'un polymère réticulé, un agent ophtalmiquement bioactif étant piégé dans ces microparticules ou microgels. Le polymère réticulé comprend un matériau ophtalmiquement acceptable d'où l'agent bioactif peut diffuser dans la lentille de contact et la traverser pour passer dans le film lacrymal présent derrière la lentille lorsque cette dernière est mise en place sur l'oeil. Le degré de polymérisation et/ou de réticulation est tel que le taux de diffusion dans la lentille de contact et de migration à travers la lentille de contact de l'agent ophtalmiquement bioactif est atténué.
PCT/US2008/010352 2007-09-04 2008-09-04 Dispersions de microparticules et de microgels dans des hydrogels pour la libération de médicaments WO2009032266A2 (fr)

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US9422315B2 (en) 2014-12-05 2016-08-23 Momentive Performance Materials Japan Llc Organosiloxane composition having high refractive index and applications containing the same
EP3092983A1 (fr) * 2013-03-15 2016-11-16 Abbott Medical Optics Inc. Portail trans-sclera pour l'administration d'agents thérapeutiques
WO2017188046A1 (fr) * 2016-04-27 2017-11-02 信越化学工業株式会社 Composé de silicone à résistance hydrolytique et son procédé de production
JP2020097603A (ja) * 2020-01-31 2020-06-25 信越化学工業株式会社 耐加水分解性シリコーン化合物及びその製造方法
US11033457B2 (en) * 2017-09-25 2021-06-15 University Of Florida Research Foundation, Inc. Preservative removal from eye drops containing hydrophilic drugs
US11179294B2 (en) 2019-12-19 2021-11-23 TearClear Corp. Preservative removal from eye drops
SE544611C2 (en) * 2018-05-18 2022-09-20 Henrik Kempe Polymer particles
SE544779C2 (en) * 2018-05-18 2022-11-15 Henrik Kempe Template-imprinted polymer particles

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