WO1995001764A2 - Ocular insert with anchoring protrusions - Google Patents

Ocular insert with anchoring protrusions Download PDF

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Publication number
WO1995001764A2
WO1995001764A2 PCT/US1994/007136 US9407136W WO9501764A2 WO 1995001764 A2 WO1995001764 A2 WO 1995001764A2 US 9407136 W US9407136 W US 9407136W WO 9501764 A2 WO9501764 A2 WO 9501764A2
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WO
WIPO (PCT)
Prior art keywords
protrusions
fornix
drug
eye
polymeric material
Prior art date
Application number
PCT/US1994/007136
Other languages
French (fr)
Other versions
WO1995001764A3 (en
Inventor
Sohrab Darougar
Alan L. Weiner
Padmanabh Pravinchandra Bhatt
Victor Albert Raul
David Clayton Gantner
Original Assignee
Sohrab Darougar
Weiner Alan L
Padmanabh Pravinchandra Bhatt
Victor Albert Raul
David Clayton Gantner
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sohrab Darougar, Weiner Alan L, Padmanabh Pravinchandra Bhatt, Victor Albert Raul, David Clayton Gantner filed Critical Sohrab Darougar
Priority to CA002165071A priority Critical patent/CA2165071C/en
Priority to EP94923238A priority patent/EP0707464A4/en
Publication of WO1995001764A2 publication Critical patent/WO1995001764A2/en
Publication of WO1995001764A3 publication Critical patent/WO1995001764A3/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F9/00Methods 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
    • A61F9/0008Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • A61K9/0051Ocular inserts, ocular implants

Definitions

  • This invention is concerned with improvements in or relating to ocular insert devices.
  • U.S. Patent No. 3,828,777 to Ness discloses an ocular device which is inserted in that portion of the eye bounded by the surfaces of the bulbar conjunctiva of the sclera of the eyeball and the palpebral conjunctiva of the lid. Such placement of the device would, however, be subject to eye movement and would not provide an anchored position such as is obtained in the present invention. Movement of the device causes pain, irritation, foreign body sensation and watering.
  • U.S. Patent No. 4,343,787 to Katz discloses water soluble inserts for the eye in which broad dimensional ranges of sizes and shapes are employed. There is no description of an insert of a specific size and shape to allow it to be retained in the fornix portion of the eye.
  • U.S. Patent No. 4,135,514 to Zaffaroni et al. relates to osmotic drug delivery devices which can be used for the administration of ocular drugs. A wide variety of shapes and sizes is disclosed.
  • EP-A-0 033 042 to Merck and Co., Inc. discloses ocular inserts which can take any of a variety of shapes, one of which may be an extruded rod. There is no description, however, of a device having dimensions which make it suitable for insertion into the fornix so as to be retained therein for 7 days or longer.
  • U.S. Patent No. 4,730,013 to Bondi et al. discloses ocular inserts intended to overcome the problem of blurred vision arising from the use of particular insert materials.
  • the maximum length of 5 mm employed by Bondi et al. is considerably smaller than the range of dimensions employed in the present invention. It is shown in the present invention that a device with a length of 5mm falls well below the minimum length required for retention in the eye of humans for 7 days or more.
  • EPO 0 251 680 to IOLAB, Inc. discloses a device for controlled drug release to the eye, in which an external matrix rapidly soluble in body fluids and having bioerodible microparticles containing the drug are positioned in the upper or lower conjunctival cul-de-sac of the eye. There is no description of a device which is retained in the eye for seven days or longer, or of the specific shape and dimension of the device of the invention for placement in the upper or lower fornix.
  • U.S. Patent No. 3,845,201 to Haddad et al. discloses an ocular device for insertion in the cul-de-sac of the conjunctiva.
  • the device may be any of various shapes, preferably disc shaped.
  • U.S. Patent No. 4,164,559 to Miyata et al. discloses a soluble device for drug delivery to the eye including a collagen insert having an ovoid shape. The device is described as insertable into the inferior fornix. There is no description of a device having the dimensions employed in the present invention for retention of seven days or longer.
  • the present invention is sometimes referred to herein as OCUFIT SR.
  • a flexible ocular insert device having a body of a thin elongated circular cylindrical configuration of specific dimensions and with anchoring protrusions of specific dimensions is well retained in place and tolerated by the patient over a prolonged period of use, for example, up to 7 to 14 days or longer.
  • the device may be inserted in the upper or lower fornix of the conjunctiva between the sclera of the eyeball and the upper or lower eyelid, being held in position preferably in the extreme outer end portion of the upper or lower fornix and prevented from moving downward or upward respectively by the pressure of the lid against the eyeball.
  • This position of the ocular insert of the present invention in the upper or lower fornix is shown in detail in the drawings as described hereinafter.
  • the device is advantageously inserted so as to fit within the upper or lower fornix by restriction of the cross sectional dimensions of the device to allow it to slip into this position and then with a length requirement that provides for anchoring the device across the lid.
  • Two or more protrusion elements extend radially outwardly from the core to minimize lateral movement when the device is positioned within the fornix.
  • the device is imperceptible to the patient, through restriction of the device to a specific size range and shape, with the upper limit not being governed by the geometric space limitation of the whole eye, and by placement specifically within the fornix, not simply within the conjunctival cul-de-sac.
  • the retention of the present insert device is independent of the movement of the eye by virtue of the fornix anatomy.
  • a device placed anywhere on the bulbar conjunctiva would be subject to eye movement and cause discomfort to the patient.
  • the insert device of the present invention must be positioned precisely and remain anchored in the upper or lower fornix, known also as the superior conjunctival fornix or the inferior conjunctival fornix, as distinct from the positioning of other kinds of devices anywhere in the conjunctival cul-de-sac.
  • the device of the present invention must be flexible to allow it to bend along the curvature of the eye within the fornix. In particular, such flexibility must be sufficient to allow it to bend along the curvature of the eye within the upper or lower fornix upon being positioned so that the longitudinal axis of the device is generally parallel to the transverse diameter of the eyeball.
  • the present insert device is imperceptible by the patient when anchored properly in the fornix, whereas prior art devices are perceived as foreign bodies. Upon proper positioning in the fornix, the present insert device is independent of eye movement and does not move when the eye moves. The device of the present invention also remains out of the field of vision. In addition, it can be placed and held in position without interference during surgical procedures.
  • the length of the present insert device is also critical to the anchoring process in the fornix.
  • the length of the device is related to the size of the eye, hence the optimum length for the human adult is 25 mm, for children is about 15 to 18 mm and for newborn babies is 8 mm in length.
  • the lengths of the upper fornix and lower fornix are about 45 to 50 mm and 35 to 40 mm respectively.
  • an insert device of the present invention with a length of up to 35 mm may remain in the upper fornix and one with a length of up to 25 mm may remain in the lower fornix without causing discomfort.
  • the invention provides, in one of its aspects, a flexible ocular insert device adapted for the controlled sustained release of an ophthalmic drug into the eye, characterized in that the device comprises a body having a thin elongated circular cylindrical configuration with at least two radially outwardly extending protrusions, the device having a length of at least 8 mm and a diameter including the protrusions not exceeding 1.9 mm.
  • the dimensions of the device according to the invention are selected as: a length of 8 to 25 mm for use in the lower fornix and a length of 8 to 35 mm for use in the upper fornix; and a diameter of 0.5 to 1.9 mm.
  • the circular cylindrical body terminates at transverse end surfaces which may for example be planar or domed.
  • the material of the insert device is for example a synthetic polymer.
  • the present invention provides a flexible ocular insert device adapted for the controlled sustained release of an ophthalmic drug into the eye, characterized in that the device comprises a body having a circular, cylindrical configuration; the length of the device is at least 8 mm and the diameter of its body including protrusions does not exceed 1.9 mm.
  • a plurality of protrusion elements extend radially outwardly from the body, with the protrusion elements being arranged in various patterns such as ribs or a screw configuration.
  • the protrusions should extend radially outwardly a distance sufficient to allow the device to become anchored in the fornix tissue. Generally, the protrusions will extend outwardly a distance such that the overall diameter of the device including the protrusions is approximately 15 to 30 percent greater than the diameter of the body or core.
  • ophthalmic drugs examples include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, tobramycin, gentamicin, erythromycin and penicillin; antibacterials such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals including idoxuridine, trifluorothymidine, acyclovir, ganciclovir and interferon; anti-allergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, cetirizine and prophenpyridadine; anti- inflammatories such as hydrocortisone, hydrocortisone a
  • the drugs may be used in conjunction with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers include solids such as starch, gelatin, sugars, e.g., glucose, natural gums, e.g., acacia, sodium alginate, carboxy-methyl cellulose, polymers, e.g., silicone rubber; liquids such as sterile water, saline, dextrose, dextrose in water or saline; condensation products of castor oil and ethylene oxide liquid glyceryl triester of a lower molecular weight fatty acid; lower alkanols; oils such as corn oil, peanut oil, sesame oil, and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxy-methylcellulose, sodium
  • the carrier may also contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents.
  • the mechanism of controlled sustained drug release into the eye is for example diffusion, osmosis or bio ⁇ erosion and these mechanisms are described for example in U.S. Patent No. 4,186,184 and in "Therapeutic Systems” by Klaus Heil ann published by Georg Thieme, Stuttgart 1978.
  • the period of controlled sustained release is for example up to 7 to 14 days or longer.
  • the configuration of the body of the insert device is tubular with its cylindrical wall closed by transverse end walls to define a reservoir for the drug which is in liquid or gel form. At least the cylindrical wall is a membrane permeable by diffusion so that the drug is released continuously at a controlled rate through the membrane into the tear fluid.
  • the configuration of the body of the insert device is tubular with domed end walls, and the device comprises a transverse impermeable elastic membrane dividing the tubular interior of the device into a first compartment and a second compartment; the first compartment is bounded by a semi-permeable membrane and the impermeable elastic membrane, and the second compartment is bounded by an impermeable material and the elastic membrane.
  • the first compartment contains a solute which cannot pass through the semi-permeable membrane and the second compartment provides a reservoir for the drug which again is in liquid or gel form.
  • the device When the device is placed in the aqueous environment of the eye water diffuses into the first compartment and stretches the elastic membrane to expand the first compartment and contract the second compartment so that the drug is forced through the drug release aperture.
  • the configuration of the body of the insert device is rod-like being constituted from a matrix of bioerodible material in which the drug is dispersed. Contact of the device with tear fluid results in controlled sustained release of the drug by bioerosion of the matrix.
  • the drug may be dispersed uniformly throughout the matrix but it is believed a more controlled release is obtained if the drug is superficially concentrated in the matrix.
  • a solid non-erodible rod with pores and dispersed drug.
  • the release of drug can take place via diffusion through the pores. Controlled release can be further regulated by gradual dissolution of solid dispersed drug within this matrix as a result of inward diffusion of aqueous solutions.
  • Examples of the materials for a permeable membrane for the diffusion mechanism include but are not limited to insoluble microporous materials of polycarbonates, polyvinyl chlorides, polyamides, copolymers of polyvinyl chloride and acrylonitrile, polyethylene, polypropylene, polysulphones, polyvinylidene fluorides, polyvinyl fluorides, polychloroethers, polyformaldehydes, acrylic resins, polyurethanes, polyimides, polybenzimadozoles, polyvinyl acetates, polyethers, cellulose esters, porous rubbers, cross-linked poly (ethylene oxide) , cross-linked polyvinyl pyrrolidone, cross-linked poly (vinyl alcohol) and polystyrenes.
  • the drug in liquid or gel form for the diffusion mechanism comprises a diffusion medium which also serves as a pharmaceutical carrier and in which the active ingredient of the drug is dissolved or suspended; the active ingredient is preferably of no more than limited solubility in the medium.
  • diffusion media include saline, glycerin, ethylene glycol, propylene glycol, water (which may also contain emulsifying and suspending agents) , mixtures of propylene glycol monostearate and oils, gum tragacanth, sodium alginate, poly(vinyl pyrrolidone) , polyoxyethylene stearate, fatty acids and silicone oil.
  • Examples of materials for an osmotic semi-permeable membrane include but are not limited to cellulose acetate and its derivatives, partial and completely hydrolyzed ethylene-vinyl acetate copolymers, highly plasticized polyvinyl chloride, homo- and copolymers of polyvinyl acetate, polyesters of acrylic acid and methacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride; silicone polycarbonates, aromatic nitrogen-containing polymeric membranes, polymeric epoxides, copolymers of an alkylene oxide and alkyl glycidyl ether, polyurethanes, polyglycolic or polyacetic acid and derivatives thereof, derivatives of polystyrene such as poly(sodium styrenesulfonate) and poly(vinyl benzyltrimethyl-ammonium chloride) , ethylene-vinyl acetate copolymers.
  • solutes which cannot pass through the semi-permeable membrane in an osmotic mechanism include but are not limited to water-soluble inorganic and organic salts and compounds such as magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfate, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, potassium acid phosphate, calcium lactate, magnesium succinate, tartaric acid, acetamide, choline chloride, soluble carbohydrates such as sorbitol, mannitol, raffinose, glucose, sucrose and lactose.
  • water-soluble inorganic and organic salts and compounds such as magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfate, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, potassium acid phosphate,
  • bioerodible matrix materials include but are not limited to polyesters of the general formula O (W) CO and mixtures thereof, wherein W is a lower alkylene of 1 to 7 carbons and may include a member selected from the group of alkylenes of the formula -CH 2 -, or -CH-CH 2 -, and Y has a value such that the molecular weight of the polymer is from about 4,000 to 100,000.
  • the polymers are polymerization-condensation products of monobasic hydroxy acid of the formula C n H 2n (OH)COOH wherein n has a value of 1 to 7, preferably 1 or 2 and the acid is especially lactic acid or glycolic acid. Also included are copolymers derived from mixtures of these acids.
  • Bioerodible materials also include poly(orthoesters) . These materials have the following general formula:
  • R ⁇ is an alkylene of 4 to 12 carbons, a cycloalkylene of 5 to 6 carbons substituted with an alkylene of 1 to 7 carbons and an alkyleneoxy of l to 7 carbons, and R 2 is a lower alkyl of 1 to 7 carbons.
  • bioerodible matrix materials which may be employed include but are not limited to the following:
  • Polyanhydrides such as poly(p-carboxyphenoxy) alkyl (e.g. p-carboxyphenoxypropane) or polymeric fatty acid dimer (e.g. poly-dodecanedioic acid) compounds and further co-polymers with sebacic acid, or phthalic acid such as disclosed in Chasin et al., Polyanhdrides for Controlled Drug Delivery, Biopharm.. February 1988, 33- 46; and Lee et al. (1988), The Use of Bioerodible Polymers and 5 fluorouracil in Glaucoma Filtration Surgery, Invest. Ophthalmol. Vis. Sci.. 29, 1692-1697;
  • non-erodible rods examples include but are not limited to polymers such as hydroxyethylmethacrylate and further co-polymers with methacrylic acid, methylmethacrylate, N-vinyl 2- pyrrolidone, allyl methacrylate, ethylene glycol dimethacrylate, ethylene dimethacrylate, or 1,1,1 trimethylopropane trimethacrylate, and dimethyl diphenyl methylvinyl polysiloxane.
  • polymers such as hydroxyethylmethacrylate and further co-polymers with methacrylic acid, methylmethacrylate, N-vinyl 2- pyrrolidone, allyl methacrylate, ethylene glycol dimethacrylate, ethylene dimethacrylate, or 1,1,1 trimethylopropane trimethacrylate, and dimethyl diphenyl methylvinyl polysiloxane.
  • Fig. 1 shows a diagrammatic sectional view of a diffusional ocular insert device embodying the invention.
  • Fig. 2 shows a diagrammatic sectional view of an osmotic ocular insert device embodying the invention.
  • Fig. 3 shows an enlarged diagrammatic sectional view of a bioerodible insert device embodying the invention.
  • Fig. 4 shows a diagrammatic sectional view of the eye with an ocular insert device of the present invention installed in the upper and lower fornix.
  • Fig. 5 shows a representation of the head of a patient with the location of the installed ocular insert device shown in dashed lines.
  • Fig. 6 shows the position of the installed ocular insert device in a closed eye.
  • Figs. 7 through 12 show diagrammatic views of further embodiments of the ocular insert device of the present invention, with various anchoring configurations.
  • Figs. 13 through 16 are graphic representations showing data in regard to drug release and swelling rate in accordance with the present invention.
  • the ocular insert device shown in Fig. 1 comprises a circular cylindrical wall 10 of a microporous synthetic polymer membrane which is insoluble in tear fluid but is permeable by diffusion.
  • the cylindrical wall 10 is closed by transverse planar end walls 12 which may be of the same microporous synthetic polymer membrane as the cylindrical wall 10 or alternatively may be impermeable.
  • the overall length of the device is 8 to 25 mm or up to 35 mm for the upper fornix and its external diameter 0.5 - 1.9 mm.
  • the cylindrical wall 10 and the end walls 12 define a reservoir for a drug which diffuses through the membrane as described hereinbefore.
  • the ocular insert device shown in Fig. 2 comprises a circular cylindrical wall 110 closed by hemispherical domed end portions 112.
  • the device also comprises, perpendicular to the axis of the cylindrical wall, an impermeable elastic membrane 114 dividing the interior of the device into a first compartment 116 and a second compartment 118.
  • the cylindrical wall 110 comprises different materials as respectively do the end walls 112 so that the first compartment is bounded by a semi- permeable synthetic polymer membrane 120 and the elastic membrane 114 and the second compartment is bounded by an impermeable synthetic polymeric membrane 122 and the elastic membrane 114.
  • the first compartment 116 contains a solute and the second compartment provides a reservoir for a drug which is forced through the aperture 124 by the stretching of the elastic membrane 114 under osmosis as described hereinbefore.
  • the ocular insert device shown in Fig. 3 comprises a circular cylindrical body 210 with domed end portions 212.
  • the device is constituted from a matrix of synthetic polymeric bioerodible material in which a drug is dispersed, being concentrated superficially of the matrix for controlled release therefrom as the matrix bioerodes.
  • the device having the configuration as shown in Fig.
  • each of the devices of Fig. 2 and Fig. 3 may also be constituted of a solid non-erodible material having pores and dispersed drug as previously discussed.
  • the overall length and diameter of each of the devices of Fig. 2 and Fig. 3 is the same as for the device of Fig. 1.
  • the ocular insert device of the present invention may be installed in the fornix by the method as follows.
  • the applicator consists of a tube with a length of about 35 mm and a flexible container with a capacity of about 500 microlitre containing a pharmaceutically acceptable viscous substance in the form of a cream:
  • the OCUFIT SR device By squeezing the container and moving the tube from one corner to another corner of the eye, the OCUFIT SR device should come out of the tube and sit between the lid and globe near the upper fornix. (f) Put tip of a finger at just about the end of the tube and hold the end of the OCUFIT SR device in position. Remove the tube.
  • the ocular insert device of the present invention Upon installation, the ocular insert device of the present invention will be positioned in the upper or lower fornix in one of the positions identified as SDRD as shown in Figs. 4 through 6 of the drawings.
  • ocular inserts having dimensions outside those of the present invention were constructed, with dimensions as follows: Size: Approximately 12x5xlmm Shape: Oval, Lower surface with concave curvature, upper surface with convex curvature Composition: Polypeptide matrix containing erythromycin estolate Consistency: Semi-rigid
  • inserts outside the scope of the present invention were placed in the upper fornix of the right eye of 16 patients between the ages of 6 and 8. The retention of the device in this location was followed over a period of 10 days. The right eye was examined twice a day for the presence of the insert. A new insert was replaced in the fornix if dislocation occurred. The results which were obtained showed that inserts of this type outside the scope of the present invention required frequent replacement into the eye over a ten day period. In no case were such inserts retained for more than 3 days at a time.
  • the drug releasing device or OCUFIT SR device of the present invention may be formed with a central, longitudinally extending body or core portion, and with two or more protrusion elements extending radially outwardly from the core.
  • the protrusion elements may be of various alternative shapes such as ribs or screw shapes so that the device may be, for example, of a ribbed design, a screw design, a bump design, a segmental design or a braided design.
  • the protrusion elements function to anchor the device in the fornix, with the tissue of the fornix filling the spaces or interstices surrounding the device between protrusions.
  • At least two protrusions should be employed, with a view toward providing an overall symmetrical shape for the device.
  • such protrusions should be evenly spaced relative to the length of the device so that the protrusions will be equidistant from their respective ends of the device.
  • the device 70 with ribbed configuration has circular cylindrical walls 72 with domed end portions 74.
  • a series of arcuate shaped ribs 76, of circular, toroidal cross section, are provided at intervals along the length of the device 70.
  • the device 70 had a core diameter "a" of 1.4 mm and with the ribs protruding outwardly from the core by a distance "b" of 0.15 mm.
  • the ribs 76 had a width "c” of 1 mm and an interval “d” between ribs 76 of 5 mm and the overall length of the device 70 was 25 mm.
  • a device 70 having a total of five ribs 76 was employed, with the space between ribs 76 being adjusted accordingly so that the ribs 76 were equally spaced apart. As few as two ribs may be employed, with one rib 76 being located adjacent each end portion of the device 70.
  • the tissue of the fornix fills the spaces or interstices surrounding the device 70 between the protrusions, which in this case are the ribs 76.
  • a device 80 with screw configuration having circular cylindrical walls 82 with domed end portions 84.
  • a series of screw-type protrusions 86 are provided at intervals along the length of the device 80.
  • the device 80 had a core diameter "a" of 1.4 mm and with the screw protrusions 86 extending outwardly from the core by a distance "b" of 0.15 mm.
  • the screw protrusions 86 had a width "c" of 1 mm and an interval “d” between protrusions 86 of 5 mm and the overall length of the device 80 was 25 mm.
  • the angle "e” was approximately 28.9 degrees in this embodiment.
  • the device 90 of Fig. 9 has a plurality of raised dimples or bumps 92 having a generally hemispherical shape on the circular cylindrical walls 94 with domed end portions 96.
  • the device 90 had a core diameter "a" of 1.4 mm and with the bumps 92 extending outwardly from the core by a distance "b" of 0.15 mm.
  • the bumps 92 had a width "c" of 1 mm and an interval "d” between bumps 92 of 5 mm and the overall length of the device 90 was 25 mm.
  • the device 100 had a core diameter "a" of 1.4 mm and with the length "c" of each segment 102 being about 1 mm.
  • the overall base width "f" of each segment 102 was 1.7 mm and the overall length of the device 100 was 25 mm.
  • the device 110 of Fig. 11 also has a segmented configuration with a series of truncated cone-shaped segments 112 interconnected along the length of the device 110 and with dome-shaped end portions 114.
  • the device 110 is formed with mirror image segmental portions 116 and 118 so that the left one-half portion 116 of the device 110 is a mirror image of the right one-half portion 118.
  • the device 110 had a core diameter "a" of 1.4 mm and with the length "c" of each segment 112 being about 1 mm.
  • the overall base width "f" of each segment 112 was 1.7 mm and the overall length of the device 110 was 25 mm.
  • the device 111 of Fig. 12 has a braided design in which a series of braided segments 113 are interconnected along the length of the device 111 and with dome shaped end portions 115.
  • the device 111 had a core diameter "a" of 1.4 mm and with the length "c" of each segment 113 being 1 mm.
  • the braided segments 113 extended outwardly from the core by a distance "b" of 0.15 mm and the overall length of the device 111 was 25 mm.
  • the ocular insert device of the present invention may be formed with a polygonal shape in cross section, with the polygon having, for example, five or six equal sides.
  • Such polygonal shape may be employed as the central core with any of the configurations shown in Figs. 7 through 12.
  • the drug loaded OCUFIT SR device can be formed by any of various processes such as extrusion molding, injection molding, transfer molding or compression molding.
  • polymer material is blended with drug at ratios of drug up to 40% by weight on a cooled two roll mill and then fed into a screw drive extruder.
  • material is continuously forced out through a coin or plate die (port) with openings conforming to the shape and dimensions of the subject device (i.e. circular) .
  • a mandrel held in place by a spider flange is positioned prior to the die.
  • the continuous noodle is pulled via conveyer belt through a heated horizontal or vertical chamber (315 to 425 degrees C) to achieve vulcanization of the material.
  • the final OCUFIT SR device is made by a cutting apparatus where the rods are cut to size. Additional modifications such as polishing the ends of the device can be accomplished.
  • the blend of polymer material and drug is placed into a heated transfer press with an aluminum or stainless steel mold containing impressions of the proper shape and size.
  • the material is forced into the mold at between 200 and 4000 psi.
  • the mold itself is kept under 10 tons of clamp pressure.
  • the mold is kept heated and under pressure at any of the following conditions:
  • the mold is cooled, separated and the formed OCUFIT SR devices are then removed.
  • silicone rubbers/elastomers are employed as the material from which the device is formed.
  • the silicone rubbers/elastomers are prepared as follows:
  • Silicone rubber prepared using dimethylsiloxane polymer or dimethyl and methylvinyl siloxane copolymers, reinforcing silica, platinum catalyst, inhibitor and siloxane crosslinker and other vulcanizing agents such as organic peroxides is either hand mixed, mixed on a two roll mill, or injection molded together with micronized drug (predominantly 10 micron particles or less) .
  • Drug is loaded into the polymer mixture at levels up to 40 weight percent of the total weight together with any other necessary excipients or release modifiers such as glycerin or sorbitol. Entrapped air within the mixture is removed by exposure to a vacuum of about 28 inches of mercury (94.8 kPa) for approximately 30 minutes. Drug is solidified within the polymer matrix by curing (vulcanizing) the mixture while being molded into the desired shape.
  • the device may also be formed of bioerodible polymers prepared as follows:
  • bioerodible polymers Polyhydroxyacids such as polylactic acid and polyglycolic acid, and polyhydroxybutyrate; Polyesters and polyorthoesters including cyclic ortho-esters with diols or diketeneacetals or diacids with diols or polyols; Polyanhydrides made from one or more of the following: p-carboxyphenoxy propane, p-carboxyphenoxy hexane, sebacic acid, dodecanedioic acid, 1,4- phenylenedipropionic acid, isophthalic acid, polypropylene fumarate and polypropylene maleate; Polypeptides; and Polycyanoacrylates) can be admixed with up to about 60% by weight of drug.
  • the material can be compressed in aluminum or stainless steel molds situated in a Carver hydraulic press at 12 tons of pressure for at least 15 minutes at 100 degrees C.
  • the device may be formed of methacrylate hydrogels prepared as follows:
  • Hydrogels loaded with drug can be constructed from crosslinked methacrylate polymers which include compositions containing one or more of the following: 2- hydroxyethyl methacrylate (HEMA) , ethylene glycol dimethacrylate, polymethylmethacrylate , methylmethacrylate, glycol monomethacrylate, ethylene monomethacrylates, glycol dimethacrylates, vinylpyrrolidone, methacrylic acid, divinylbenzene, and alkyldiol methacrylates, acrylamide, methylene bis acrylamide.
  • HEMA 2- hydroxyethyl methacrylate
  • crosslinking percentages can be achieved by altering the ratios of the copolymers. For example a 40:1 weight ratio of acrylamide to methylene bis acrylamide produces a 2.5% crosslinking. A buffered solution (pH 7-9) of the copolymers is made containing the desired crosslinking ratio. The final total polymer percentage can be varied from 1 to 25%. Drug is admixed into this solution. Suitable crosslinking free radical generator and catalyst (such as ammonium persulfate and tetra methyl ethylene diamine) is added. The mixture is poured into an appropriate mold with the desired shape. Polymerization occurs within 30 minutes.
  • Suitable crosslinking free radical generator and catalyst such as ammonium persulfate and tetra methyl ethylene diamine
  • inventions of the invention may employ the ophthalmic drugs and pharmaceutically acceptable carriers as previously described.
  • silastic MDX4-4210 curing agent (Dow Corning Corp, Midland, MI) was mixed with 10 parts of MDX4-4210 silastic base elastomer (Dow Corning Corp, Midland, MI) .
  • Oxytetracycline hydrochloride (Sigma Chemical Co., St. Louis) in the amount of 1% by weight of the total mixture was thoroughly blended in with care taken to minimize entrapment of air.
  • the material was placed under vacuum of about 28 inches of mercury (94.8 kPa) for 30 minutes. Material was then transfered into a cylinder situated in a transfer press.
  • the material was then forced into a 12 cavity aluminum mold heated to 135 degrees C which contained impressions of the ribbed device design and forced into the mold at a transfer pressure of 400 psi (2757.9 kPa) .
  • the mold itself was kept under 10 tons of clamp pressure for 3.5 minutes.
  • the mold was cooled, separated and the formed devices were removed.
  • Silastic MDX4-4210 curing agent (Dow Corning Corp, Midland, MI) was mixed with 10 parts of MDX4-4210 Silastic base elastomer (Dow Corning Corp, Midland, MI) .
  • Oxytetracycline hydrochloride (Sigma Chemical Co., St. Louis) in the amount of 20% by weight of the total mixture was thoroughly blended in with care taken to minimize entrapment of air.
  • the material was placed under vacuum of about 28 inches of mercury (94.8 kPa) for 30 minutes. Material was then transfered into a cylinder situated in a transfer press.
  • the material was then forced into a 12 cavity aluminum mold heated to 121 degrees C which contained impressions of the ribbed device design and forced into the mold at a transfer pressure of 800 psi (5515.8 kPa) .
  • the mold itself was kept under 10 tons of clamp pressure for 3.25 minutes. The mold was cooled, separated and the formed devices were removed.
  • Silastic medical grade ETR elastomer Q7-4720 (Dow Corning Corp, Midland, MI) was prepared by first individually softening Part B and Part A of the elastomer on a cooled two-roll mill. The two components were then blended together in a 1:1 ratio on the two-roll mill. Material was then transfered into a cylinder situated in a transfer press. The material was then forced into a 12 cavity aluminum mold heated to 121 degrees C at a transfer pressure of 800 psi (5515.8 kPa) . The mold itself was kept under 10 tons of clamp pressure for 3.25 minutes. The mold was cooled, separated and the formed devices were removed.
  • Silastic medical grade ETR elastomer LSR 76000 (Dow Corning Corp. , Midland, MI) was prepared by first individually softening Part B and Part A of the elastomer on a cooled two-roll mill. The two components were then blended together in a 1:1 ratio on the two-roll mill. Oxytetracycline hydrochloride with or without USP grade dextrose premixed in various ratios was added incrementally into the blend to assure homogeneous distribution. Material was then transferred into a cylinder situated in a transfer press. The material was then forced into a 12 cavity aluminum mold heated to 121°C at a transfer pressure of 800 psi (5515.8 kPa) . The mold itself was kept under 10 tons of clamp pressure for 3.25 minutes. The mold was cooled, separated and the formed devices were removed.
  • Example 7 For control devices not containing any protrusion beyond the core, simple cylindrical rods were prepared as in Example 1 except using a mold with impressions of a simple rod shape.
  • eye ointment such as Neosporin, Burroughs Wellcome, Research Triangle Park, NC
  • the configuration of the ribbed OCUFIT SR device was as shown in Fig. 7 of the drawings but with five ribs.
  • the material employed was a solid silastic based material
  • MDX4-4210 a medical grade elastomer. No drug was incorporated into the OCUFIT SR device and the ends of the device were rounded.
  • the method used in this study was as follows: The volunteer was asked to sit down, hold his/her chin slightly up and to look down continuously throughout the exercise.
  • the eye was anaesthetized by a drop of Benoxenate
  • the upper lid was separated from the globe by about 4 to 5 millimeters by holding lashes and gently pulling the lid backward and upward.
  • the OCUFIT SR device held in the forceps was centrally located at a midpoint between the nasal and temporal canthus and was pushed under the upper lid inward about 6 to 7 mm.
  • the tip of a finger was positioned in the middle of the eyelid just above the end of the forceps before the OCUFIT SR device was released and forceps removed. The device was released and the ends of the device were allowed to orient toward the respective canthus. With the tip of a finger the OCUFIT SR device was gently pushed upward and toward the deep fornix. The maneuver was repeated twice more in each corner (canthus) .
  • the volunteer was asked to move the eye downward and upward three times. The volunteer was advised:
  • the eyes were examined by a slit lamp.
  • the clinical signs of the conjunctiva, cornea and anterior uvea were recorded on a specially designed proforma.
  • the duration of retention was planned for four weeks.
  • a mechanical insertion device may be employed for insertion of the device of the present invention.
  • the OCUFIT SR device was inserted once and in one volunteer (MMR) it was inserted twice.
  • the OCUFIT SR device was inserted in the upper fornix of the left eye in 8 volunteers and in the upper fornix of the right eye in one volunteer (RMW) .
  • the period of retention for each volunteer is shown in Table 2.
  • the OCUFIT SR device was retained for 24 days or more. Of these, five retained the device for 28 days or longer before it was removed and in one volunteer (case 7, MG) the OCUFIT SR device came out on day 24 for no apparent reason.
  • the first OCUFIT SR device came out on day 11 after vigorous physical exercise.
  • the second OCUFIT SR device in this volunteer retained well for 32 days before it was removed.
  • three volunteers (cases 2,4 and 9) the OCUFIT SR device retained between 3 and 5 days respectively.
  • OCUFIT SR device was rejected after rubbing of the eye and in case 9, it came out from the outer corner of the eye for no apparent reason.
  • Figs. 13 and 14 there are provided various graphs showing drug release data in accordance with the present invention.
  • a Q7-4735 elastomer was employed and the desired or theoretical release rate for efficacy is shown as well as results obtained when the device was loaded with oxytetracycline in an amount of 10% of the weight of the unloaded device.
  • Fig. 14 The data in Fig. 14 is for various amounts of loading of oxytetracycline in a device formed of the MDX4-4210 elastomer, with Fig. 14 showing results over a 24 hour period.
  • Fig. 15 shows a graph of drug release data in accordance with the present invention, in which dextrose is employed as a release modifier. As shown in the graph, the solids percentage is maintained at 30% and the amount of dextrose is varied between 0 and 15%, as shown in the different curves. By adding dextrose, more pores or pathways are created for drug diffusion. These drugs are employed with suitable carriers as previously discussed.
  • Fig. 16 there is shown a graph of the swelling rate of a particular elastomer employed in a device of the present invention.
  • Swelling is caused by the migration of water into the polymer, dissolving the drug and causing the polymer to swell due to an osmotic effect as water forces the polymer outwardly.
  • Such swelling can be desirable inasmuch as a device of the present invention may lock into place as it grows in size. It has been found that the silicone materials are particularly prone to swell in this manner.
  • Fig. 16 there are shown the measurements obtained with regard to swelling of a device of the present invention which has been loaded with oxytetracycline and dextrose. At large drug loads, the device can swell so that both length and diameter are increased significantly.
  • Table 3 show physical properties, including tensile strength and % elongation for a device of the present invention prepared in various formulations with various amounts of oxytetracycline, glycerine and polyethlene glycol.

Abstract

A flexible ocular insert device adapted for the controlled sustained release of an ophthalmic drug into the eye. In one embodiment, the device includes an elongated body of a polymeric material in the form of a rod or tube containing a pharmaceutically active ingredient and with at least two anchoring protrusions extending radially outwardly from the body. The device has a length of at least 8 mm and the diameter of its body portion including the protrusions does not exceed 1.9 mm. As shown in Figure 7, the device (70) with ribbed configuration has circular cylindrical walls (72) with domed end portions (74). A series of arcuate shaped ribs (76), of circular, toroidal cross section, are provided at intervals along the length of the device (70).

Description

OCULAR INSERT WITH ANCHORING PROTRUSIONS
TECHNICAL FIELD
This invention is concerned with improvements in or relating to ocular insert devices.
BACKGROUND ART Various diseases of the eye are commonly treated by frequent daily application of ophthalmic drugs for example in the form of eye drops or ointment. While this is suitable and convenient in some cases, it can be a serious disadvantage that the drug is not present in the eye in a continuous manner. With a view to overcoming this disadvantage it has been previously proposed, for example, in U.S. Patent No. 3,416,530 of R.A. Ness assigned to Alza Corporation and subsequent patents of Alza Corporation to provide a flexible ocular insert device adapted for the controlled sustained release of the drug.
In for example U.S. Patent No. 3,828,777 of R.A. Ness assigned to Alza Corporation it is stated that the ocular insert can be fabricated in any convenient shape for comfortable retention in the conjunctival sac of the eye and that the marginal outline can be ellipsoid, doughnut-shape, bean-shape, banana-shape, circular or rectangular; and in cross section it can be doubly convex, concavoconve , or rectangular. It is suggested however that the original cross-sectional shape of the device is not of controlling importance. However, these previously proposed devices have in practice met with no more than limited success because most of the proposed shapes and sizes were not suitable for placement in the narrow upper and lower fornices. Also previous devices have tended not to remain in place in the eye and have at times caused irritation to the patient during use. U.S. Patent No. 4,186,184 to A. Zaffaroni discloses that the length of an insert device should be from 2 to
20 mm, its width 1 to 15 mm and its thickness 0.1 to 4 mm. A wide variety of shapes are disclosed, including ellipsoid, doughnut, bean, banana and square shapes.
U.S. Patent No. 3,828,777 to Ness discloses an ocular device which is inserted in that portion of the eye bounded by the surfaces of the bulbar conjunctiva of the sclera of the eyeball and the palpebral conjunctiva of the lid. Such placement of the device would, however, be subject to eye movement and would not provide an anchored position such as is obtained in the present invention. Movement of the device causes pain, irritation, foreign body sensation and watering. U.S. Patent No. 4,343,787 to Katz discloses water soluble inserts for the eye in which broad dimensional ranges of sizes and shapes are employed. There is no description of an insert of a specific size and shape to allow it to be retained in the fornix portion of the eye. U.S. Patent No. 4,135,514 to Zaffaroni et al. relates to osmotic drug delivery devices which can be used for the administration of ocular drugs. A wide variety of shapes and sizes is disclosed.
EP-A-0 033 042 to Merck and Co., Inc. discloses ocular inserts which can take any of a variety of shapes, one of which may be an extruded rod. There is no description, however, of a device having dimensions which make it suitable for insertion into the fornix so as to be retained therein for 7 days or longer. U.S. Patent No. 4,730,013 to Bondi et al. discloses ocular inserts intended to overcome the problem of blurred vision arising from the use of particular insert materials. The maximum length of 5 mm employed by Bondi et al. is considerably smaller than the range of dimensions employed in the present invention. It is shown in the present invention that a device with a length of 5mm falls well below the minimum length required for retention in the eye of humans for 7 days or more.
EPO 0 251 680 to IOLAB, Inc. discloses a device for controlled drug release to the eye, in which an external matrix rapidly soluble in body fluids and having bioerodible microparticles containing the drug are positioned in the upper or lower conjunctival cul-de-sac of the eye. There is no description of a device which is retained in the eye for seven days or longer, or of the specific shape and dimension of the device of the invention for placement in the upper or lower fornix.
U.S. Patent No. 3,845,201 to Haddad et al. discloses an ocular device for insertion in the cul-de-sac of the conjunctiva. The device may be any of various shapes, preferably disc shaped.
U.S. Patent No. 4,164,559 to Miyata et al. discloses a soluble device for drug delivery to the eye including a collagen insert having an ovoid shape. The device is described as insertable into the inferior fornix. There is no description of a device having the dimensions employed in the present invention for retention of seven days or longer.
U.S. Patent No. 4,179,497 to Cohen et al. discloses water soluble inserts of various shapes for applying drugs to the cul-de-sac of the conjunctiva. Again there is no description of an insert having the specific dimensions of the invention.
In the use of a prior art device known as Ocusert, the subject of U.S. Patent No. 3,828,777 to Ness, the device is inserted into the conjunctival cul-de-sac. Either of two systems may be employed, with the Pilo-20 system measuring 5.7x13.4 mm on its axes and 0.3 mm in thickness and the Pilo-40 system measuring 5.5x13mm on its axes and 0.5 mm in thickness. Various problems in retention and irritation which occurred in the use of this device are documented, for example, in the following publications: P. Sihvola et al.. Practical problems in the use of Ocusert-pilocarpine delivery system, Acta Ophthalmol. fCopenh.) . Dec. 1980, 58 (6), pp 933-937; S.E. Smith et al., Comparison of the pupillary, refractive and hypotensive effects of Ocusert-40 and pilocarpine eyedrops in the treatment of chronic simple glaucoma, Br. J. Ophthalmol.. April 1979, 63(4) pp 228-232; and I.P. Pollack et al.. The Ocusert pilocarpine system: advantages and disadvantages, South Med. J.. October 1976, 69 (10), pp 1296-1298. Other ocular inserts are described in the following literature reports: Urtti et al. (1990) Controlled drug delivery devices for experimental ocular studies with timolol.l.In vitro release studies. Int. J. Pharm.. 61, 235-240; and Urtti et al (1990) Controlled drug delivery devices for experimental ocular studies with timolol.2.Ocular and systemic absorption in rabbits. Int. J. Pharm.. 61, 241-249. These reports describe the use of a permeable hollow tube (silicone) for ocular delivery. The tube has a diameter of 1.94 mm which is outside the dimensions employed in the present invention. Also, the device was only observed in the eye for an 8 hour period.
DISCLOSURE OF INVENTION It is an object of the present invention to provide an improved ocular insert device adapted for the controlled sustained release of a drug. The present invention is sometimes referred to herein as OCUFIT SR.
It has been found, in accordance with the present invention, that a flexible ocular insert device having a body of a thin elongated circular cylindrical configuration of specific dimensions and with anchoring protrusions of specific dimensions is well retained in place and tolerated by the patient over a prolonged period of use, for example, up to 7 to 14 days or longer. The device may be inserted in the upper or lower fornix of the conjunctiva between the sclera of the eyeball and the upper or lower eyelid, being held in position preferably in the extreme outer end portion of the upper or lower fornix and prevented from moving downward or upward respectively by the pressure of the lid against the eyeball. This position of the ocular insert of the present invention in the upper or lower fornix is shown in detail in the drawings as described hereinafter.
In particular, the device is advantageously inserted so as to fit within the upper or lower fornix by restriction of the cross sectional dimensions of the device to allow it to slip into this position and then with a length requirement that provides for anchoring the device across the lid. Two or more protrusion elements extend radially outwardly from the core to minimize lateral movement when the device is positioned within the fornix. By locating the device within the fornix, the device is imperceptible to the patient, through restriction of the device to a specific size range and shape, with the upper limit not being governed by the geometric space limitation of the whole eye, and by placement specifically within the fornix, not simply within the conjunctival cul-de-sac. In addition, the retention of the present insert device is independent of the movement of the eye by virtue of the fornix anatomy. In contrast, a device placed anywhere on the bulbar conjunctiva would be subject to eye movement and cause discomfort to the patient.
The insert device of the present invention must be positioned precisely and remain anchored in the upper or lower fornix, known also as the superior conjunctival fornix or the inferior conjunctival fornix, as distinct from the positioning of other kinds of devices anywhere in the conjunctival cul-de-sac. The device of the present invention must be flexible to allow it to bend along the curvature of the eye within the fornix. In particular, such flexibility must be sufficient to allow it to bend along the curvature of the eye within the upper or lower fornix upon being positioned so that the longitudinal axis of the device is generally parallel to the transverse diameter of the eyeball.
The present insert device is imperceptible by the patient when anchored properly in the fornix, whereas prior art devices are perceived as foreign bodies. Upon proper positioning in the fornix, the present insert device is independent of eye movement and does not move when the eye moves. The device of the present invention also remains out of the field of vision. In addition, it can be placed and held in position without interference during surgical procedures.
The length of the present insert device is also critical to the anchoring process in the fornix. The length of the device is related to the size of the eye, hence the optimum length for the human adult is 25 mm, for children is about 15 to 18 mm and for newborn babies is 8 mm in length.
In general, for adults, the lengths of the upper fornix and lower fornix are about 45 to 50 mm and 35 to 40 mm respectively. Thus an insert device of the present invention with a length of up to 35 mm may remain in the upper fornix and one with a length of up to 25 mm may remain in the lower fornix without causing discomfort. The invention provides, in one of its aspects, a flexible ocular insert device adapted for the controlled sustained release of an ophthalmic drug into the eye, characterized in that the device comprises a body having a thin elongated circular cylindrical configuration with at least two radially outwardly extending protrusions, the device having a length of at least 8 mm and a diameter including the protrusions not exceeding 1.9 mm. Advantageously the dimensions of the device according to the invention are selected as: a length of 8 to 25 mm for use in the lower fornix and a length of 8 to 35 mm for use in the upper fornix; and a diameter of 0.5 to 1.9 mm.
The circular cylindrical body terminates at transverse end surfaces which may for example be planar or domed.
The material of the insert device is for example a synthetic polymer. The present invention provides a flexible ocular insert device adapted for the controlled sustained release of an ophthalmic drug into the eye, characterized in that the device comprises a body having a circular, cylindrical configuration; the length of the device is at least 8 mm and the diameter of its body including protrusions does not exceed 1.9 mm. A plurality of protrusion elements extend radially outwardly from the body, with the protrusion elements being arranged in various patterns such as ribs or a screw configuration. The protrusions should extend radially outwardly a distance sufficient to allow the device to become anchored in the fornix tissue. Generally, the protrusions will extend outwardly a distance such that the overall diameter of the device including the protrusions is approximately 15 to 30 percent greater than the diameter of the body or core.
Examples of ophthalmic drugs include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, tobramycin, gentamicin, erythromycin and penicillin; antibacterials such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals including idoxuridine, trifluorothymidine, acyclovir, ganciclovir and interferon; anti-allergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, cetirizine and prophenpyridadine; anti- inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone , dexamethasone 21-phosphate, fluocinolone, edrysone, prednisolone acetate, fluoromethalone, betamethasone, and tria cinolone and non-steroidal agents such as indomethacin, diclofenac, flurbiprofen, piroxicam, ibuprofen and acetyl salicylic acid; decongestants such as phenylephrine, naphazoline and tetrahydrozoline: miotics and anticholinesterase such as pilocarpine, acetylcholine chloride, physostigmine, eserine, carbachol, di-isopropyl fluorophosphate, phospholine iodine, and demecariu bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; sympathomimetics such as epinephrine; immunological drugs such as vaccines and immune stimulants; hormonal agents such as estrogens, estradiol, progestational, progesterone,insulin, calcitonin, parathyroid hormone and peptide, vasopressin, hypothalamus releasing factor; beta adrenergic blockers such as timolol maleate, levobunolol HC1 and betaxolol HC1; growth factors such as epidermal growth factor and fibronectin; carbonic anhydrase inhibitors such as dichlorphenamide, acetazolamide and methazolamide and other drugs such as prostaglandins, antiprostaglandins, and prostaglandin precursors.
The drugs may be used in conjunction with a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include solids such as starch, gelatin, sugars, e.g., glucose, natural gums, e.g., acacia, sodium alginate, carboxy-methyl cellulose, polymers, e.g., silicone rubber; liquids such as sterile water, saline, dextrose, dextrose in water or saline; condensation products of castor oil and ethylene oxide liquid glyceryl triester of a lower molecular weight fatty acid; lower alkanols; oils such as corn oil, peanut oil, sesame oil, and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxy-methylcellulose, sodium alginate, poly(vinylpyrolidone) , alone, or with suitable dispensing agents such as lecithin, polyoxyethylene stearate. The carrier may also contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents. The mechanism of controlled sustained drug release into the eye is for example diffusion, osmosis or bio¬ erosion and these mechanisms are described for example in U.S. Patent No. 4,186,184 and in "Therapeutic Systems" by Klaus Heil ann published by Georg Thieme, Stuttgart 1978. The period of controlled sustained release is for example up to 7 to 14 days or longer.
In one exemplary embodiment of the present invention utilizing the diffusion mechanism, the configuration of the body of the insert device is tubular with its cylindrical wall closed by transverse end walls to define a reservoir for the drug which is in liquid or gel form. At least the cylindrical wall is a membrane permeable by diffusion so that the drug is released continuously at a controlled rate through the membrane into the tear fluid. In one exemplary embodiment of the invention utilizing the osmosis mechanism, the configuration of the body of the insert device is tubular with domed end walls, and the device comprises a transverse impermeable elastic membrane dividing the tubular interior of the device into a first compartment and a second compartment; the first compartment is bounded by a semi-permeable membrane and the impermeable elastic membrane, and the second compartment is bounded by an impermeable material and the elastic membrane. There is a drug release aperture in the impermeable end wall of the device.
The first compartment contains a solute which cannot pass through the semi-permeable membrane and the second compartment provides a reservoir for the drug which again is in liquid or gel form. When the device is placed in the aqueous environment of the eye water diffuses into the first compartment and stretches the elastic membrane to expand the first compartment and contract the second compartment so that the drug is forced through the drug release aperture.
In one exemplary embodiment of the invention utilizing the bioerosion mechanism, the configuration of the body of the insert device is rod-like being constituted from a matrix of bioerodible material in which the drug is dispersed. Contact of the device with tear fluid results in controlled sustained release of the drug by bioerosion of the matrix. The drug may be dispersed uniformly throughout the matrix but it is believed a more controlled release is obtained if the drug is superficially concentrated in the matrix.
In another embodiment of the invention, there is employed a solid non-erodible rod with pores and dispersed drug. The release of drug can take place via diffusion through the pores. Controlled release can be further regulated by gradual dissolution of solid dispersed drug within this matrix as a result of inward diffusion of aqueous solutions. Examples of the materials for a permeable membrane for the diffusion mechanism include but are not limited to insoluble microporous materials of polycarbonates, polyvinyl chlorides, polyamides, copolymers of polyvinyl chloride and acrylonitrile, polyethylene, polypropylene, polysulphones, polyvinylidene fluorides, polyvinyl fluorides, polychloroethers, polyformaldehydes, acrylic resins, polyurethanes, polyimides, polybenzimadozoles, polyvinyl acetates, polyethers, cellulose esters, porous rubbers, cross-linked poly (ethylene oxide) , cross-linked polyvinyl pyrrolidone, cross-linked poly (vinyl alcohol) and polystyrenes.
The drug in liquid or gel form for the diffusion mechanism comprises a diffusion medium which also serves as a pharmaceutical carrier and in which the active ingredient of the drug is dissolved or suspended; the active ingredient is preferably of no more than limited solubility in the medium. Examples of diffusion media include saline, glycerin, ethylene glycol, propylene glycol, water (which may also contain emulsifying and suspending agents) , mixtures of propylene glycol monostearate and oils, gum tragacanth, sodium alginate, poly(vinyl pyrrolidone) , polyoxyethylene stearate, fatty acids and silicone oil.
Examples of materials for an osmotic semi-permeable membrane include but are not limited to cellulose acetate and its derivatives, partial and completely hydrolyzed ethylene-vinyl acetate copolymers, highly plasticized polyvinyl chloride, homo- and copolymers of polyvinyl acetate, polyesters of acrylic acid and methacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride; silicone polycarbonates, aromatic nitrogen-containing polymeric membranes, polymeric epoxides, copolymers of an alkylene oxide and alkyl glycidyl ether, polyurethanes, polyglycolic or polyacetic acid and derivatives thereof, derivatives of polystyrene such as poly(sodium styrenesulfonate) and poly(vinyl benzyltrimethyl-ammonium chloride) , ethylene-vinyl acetate copolymers.
Examples of solutes which cannot pass through the semi-permeable membrane in an osmotic mechanism include but are not limited to water-soluble inorganic and organic salts and compounds such as magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfate, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, potassium acid phosphate, calcium lactate, magnesium succinate, tartaric acid, acetamide, choline chloride, soluble carbohydrates such as sorbitol, mannitol, raffinose, glucose, sucrose and lactose.
Examples of bioerodible matrix materials include but are not limited to polyesters of the general formula O (W) CO and mixtures thereof, wherein W is a lower alkylene of 1 to 7 carbons and may include a member selected from the group of alkylenes of the formula -CH2-, or -CH-CH2-, and Y has a value such that the molecular weight of the polymer is from about 4,000 to 100,000. The polymers are polymerization-condensation products of monobasic hydroxy acid of the formula CnH2n(OH)COOH wherein n has a value of 1 to 7, preferably 1 or 2 and the acid is especially lactic acid or glycolic acid. Also included are copolymers derived from mixtures of these acids. Bioerodible materials also include poly(orthoesters) . These materials have the following general formula:
Figure imgf000014_0001
wherein Rα is an alkylene of 4 to 12 carbons, a cycloalkylene of 5 to 6 carbons substituted with an alkylene of 1 to 7 carbons and an alkyleneoxy of l to 7 carbons, and R2 is a lower alkyl of 1 to 7 carbons.
Other bioerodible matrix materials which may be employed include but are not limited to the following:
(1) Polyanhydrides such as poly(p-carboxyphenoxy) alkyl (e.g. p-carboxyphenoxypropane) or polymeric fatty acid dimer (e.g. poly-dodecanedioic acid) compounds and further co-polymers with sebacic acid, or phthalic acid such as disclosed in Chasin et al., Polyanhdrides for Controlled Drug Delivery, Biopharm.. February 1988, 33- 46; and Lee et al. (1988), The Use of Bioerodible Polymers and 5 fluorouracil in Glaucoma Filtration Surgery, Invest. Ophthalmol. Vis. Sci.. 29, 1692-1697;
(2) Poly (alky1-2-cyanoacrylates) such as poly (hexyl-2- cyanoacrylate) as described by Douglas et al. (1987) , Nanoparticles in Drug Delivery, CRC Crit. Rev. Therap. Drug Carr. Svst.. 3, 233-261; and (3) Polyamino acids such as copolymers of leucine and methyl glutamate.
Further information on membrane and bioerodible materials is contained in U.S. Patents Nos. 3,828,777 and 4,186,184 and also the following references: Leong and Langer (1987) , Polymeric Controlled Drug Delivery, Adv. Drug Del. Rev.. 1, 199-233; and Smith et al. (1990), Bioerodible Polymers for Delivery of Macromolecules, Adv. Drug Del. Rev.. 4, 343-357. Examples of materials for use as non-erodible rods include but are not limited to polymers such as hydroxyethylmethacrylate and further co-polymers with methacrylic acid, methylmethacrylate, N-vinyl 2- pyrrolidone, allyl methacrylate, ethylene glycol dimethacrylate, ethylene dimethacrylate, or 1,1,1 trimethylopropane trimethacrylate, and dimethyl diphenyl methylvinyl polysiloxane.
The above and other aspects of the present invention will become more clear from the following description, to be read with reference to the accompanying drawings of devices embodying the invention. This description is given by way of example only, and not by the way of limitation of the invention.
BRIEF DESCRIPTION OF DRAWINGS
In the accompanying drawings:
Fig. 1 shows a diagrammatic sectional view of a diffusional ocular insert device embodying the invention. Fig. 2 shows a diagrammatic sectional view of an osmotic ocular insert device embodying the invention.
Fig. 3 shows an enlarged diagrammatic sectional view of a bioerodible insert device embodying the invention.
Fig. 4 shows a diagrammatic sectional view of the eye with an ocular insert device of the present invention installed in the upper and lower fornix.
Fig. 5 shows a representation of the head of a patient with the location of the installed ocular insert device shown in dashed lines. Fig. 6 shows the position of the installed ocular insert device in a closed eye.
Figs. 7 through 12 show diagrammatic views of further embodiments of the ocular insert device of the present invention, with various anchoring configurations.
Figs. 13 through 16 are graphic representations showing data in regard to drug release and swelling rate in accordance with the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
The ocular insert device shown in Fig. 1 comprises a circular cylindrical wall 10 of a microporous synthetic polymer membrane which is insoluble in tear fluid but is permeable by diffusion. The cylindrical wall 10 is closed by transverse planar end walls 12 which may be of the same microporous synthetic polymer membrane as the cylindrical wall 10 or alternatively may be impermeable. The overall length of the device is 8 to 25 mm or up to 35 mm for the upper fornix and its external diameter 0.5 - 1.9 mm.
The cylindrical wall 10 and the end walls 12 define a reservoir for a drug which diffuses through the membrane as described hereinbefore.
The ocular insert device shown in Fig. 2 comprises a circular cylindrical wall 110 closed by hemispherical domed end portions 112. The device also comprises, perpendicular to the axis of the cylindrical wall, an impermeable elastic membrane 114 dividing the interior of the device into a first compartment 116 and a second compartment 118. The cylindrical wall 110 comprises different materials as respectively do the end walls 112 so that the first compartment is bounded by a semi- permeable synthetic polymer membrane 120 and the elastic membrane 114 and the second compartment is bounded by an impermeable synthetic polymeric membrane 122 and the elastic membrane 114. There is an axial drug release aperture 124 in the membrane 122 at the domed end portion 112 thereof.
The first compartment 116 contains a solute and the second compartment provides a reservoir for a drug which is forced through the aperture 124 by the stretching of the elastic membrane 114 under osmosis as described hereinbefore.
The ocular insert device shown in Fig. 3 comprises a circular cylindrical body 210 with domed end portions 212. The device is constituted from a matrix of synthetic polymeric bioerodible material in which a drug is dispersed, being concentrated superficially of the matrix for controlled release therefrom as the matrix bioerodes.
The device having the configuration as shown in Fig.
3 may also be constituted of a solid non-erodible material having pores and dispersed drug as previously discussed. The overall length and diameter of each of the devices of Fig. 2 and Fig. 3 is the same as for the device of Fig. 1.
The ocular insert device of the present invention may be installed in the fornix by the method as follows. The applicator consists of a tube with a length of about 35 mm and a flexible container with a capacity of about 500 microlitre containing a pharmaceutically acceptable viscous substance in the form of a cream:
(a) Insert the OCUFIT SR device into the tube. Squeeze the container until the viscous substance pushes the device into the mouth of the tube.
(b) Ask the patient to sit down and hold his/her chin slightly up.
(c) Ask the patient to look down continuously throughout the exercise.
(d) Separate the upper lid from the globe by about
4 to 5mm by holding the lashes and gently pulling the lid forward and upward. Insert the tube under the eyelid for about 5mm near the inner corner (nasal canthus) of the eye. Do not touch the inner corner of the eye and the globe.
(e) Push out the OCUFIT SR device by squeezing the container gently and continuously. In the meantime move the tube slowly from the inner corner (nasal canthus) toward the outer corner (temporal canthus) , holding the tip of the tube at about 5mm from the lid margin constantly. Stop about 5mm from the outer corner.
N.B. By squeezing the container and moving the tube from one corner to another corner of the eye, the OCUFIT SR device should come out of the tube and sit between the lid and globe near the upper fornix. (f) Put tip of a finger at just about the end of the tube and hold the end of the OCUFIT SR device in position. Remove the tube.
(g) With the help of the tip of a finger, gently push the OCUFIT SR device upward and toward the deep fornix. Repeat the movement twice more, once in the middle of the lid and once near the inner corner.
(h) Ask the patient to move the eye upward and downward three times. Make sure that the device is in position and is not coming out. The device may also be installed directly by the patient using similar procedures as described above.
Upon installation, the ocular insert device of the present invention will be positioned in the upper or lower fornix in one of the positions identified as SDRD as shown in Figs. 4 through 6 of the drawings.
By the way of comparison, ocular inserts having dimensions outside those of the present invention were constructed, with dimensions as follows: Size: Approximately 12x5xlmm Shape: Oval, Lower surface with concave curvature, upper surface with convex curvature Composition: Polypeptide matrix containing erythromycin estolate Consistency: Semi-rigid
These inserts outside the scope of the present invention were placed in the upper fornix of the right eye of 16 patients between the ages of 6 and 8. The retention of the device in this location was followed over a period of 10 days. The right eye was examined twice a day for the presence of the insert. A new insert was replaced in the fornix if dislocation occurred. The results which were obtained showed that inserts of this type outside the scope of the present invention required frequent replacement into the eye over a ten day period. In no case were such inserts retained for more than 3 days at a time.
The foregoing comparative tests show the importance of employing an ocular insert device having the size and shape as described herein.
In further embodiments of the invention, as shown in Figs. 7 through 12, the drug releasing device or OCUFIT SR device of the present invention may be formed with a central, longitudinally extending body or core portion, and with two or more protrusion elements extending radially outwardly from the core. The protrusion elements may be of various alternative shapes such as ribs or screw shapes so that the device may be, for example, of a ribbed design, a screw design, a bump design, a segmental design or a braided design. The protrusion elements function to anchor the device in the fornix, with the tissue of the fornix filling the spaces or interstices surrounding the device between protrusions.
At least two protrusions should be employed, with a view toward providing an overall symmetrical shape for the device. In a case where only two protrusions are employed, such protrusions should be evenly spaced relative to the length of the device so that the protrusions will be equidistant from their respective ends of the device. Where more than two protrusions are employed, it is important to provide a symmetrical arrangement with even spacing so as to achieve a uniform anchoring function along the length of the device. As shown in Fig. 7, the device 70 with ribbed configuration has circular cylindrical walls 72 with domed end portions 74. A series of arcuate shaped ribs 76, of circular, toroidal cross section, are provided at intervals along the length of the device 70. In one embodiment, the device 70 had a core diameter "a" of 1.4 mm and with the ribs protruding outwardly from the core by a distance "b" of 0.15 mm. In this embodiment, the ribs 76 had a width "c" of 1 mm and an interval "d" between ribs 76 of 5 mm and the overall length of the device 70 was 25 mm.
In another embodiment similar to that of Fig. 7, a device 70 having a total of five ribs 76 was employed, with the space between ribs 76 being adjusted accordingly so that the ribs 76 were equally spaced apart. As few as two ribs may be employed, with one rib 76 being located adjacent each end portion of the device 70. In these embodiments as with those embodiments described hereinafter, the tissue of the fornix fills the spaces or interstices surrounding the device 70 between the protrusions, which in this case are the ribs 76.
In Fig. 8 there is shown a device 80 with screw configuration having circular cylindrical walls 82 with domed end portions 84. A series of screw-type protrusions 86 are provided at intervals along the length of the device 80. In one embodiment, the device 80 had a core diameter "a" of 1.4 mm and with the screw protrusions 86 extending outwardly from the core by a distance "b" of 0.15 mm. In this embodiment, the screw protrusions 86 had a width "c" of 1 mm and an interval "d" between protrusions 86 of 5 mm and the overall length of the device 80 was 25 mm. The angle "e" was approximately 28.9 degrees in this embodiment.
The device 90 of Fig. 9 has a plurality of raised dimples or bumps 92 having a generally hemispherical shape on the circular cylindrical walls 94 with domed end portions 96. In one embodiment, the device 90 had a core diameter "a" of 1.4 mm and with the bumps 92 extending outwardly from the core by a distance "b" of 0.15 mm. In this embodiment, the bumps 92 had a width "c" of 1 mm and an interval "d" between bumps 92 of 5 mm and the overall length of the device 90 was 25 mm. There were four longitudinally aligned rows of bumps 92 equally spaced about the circumference of the device 90 in this embodiment. The number of rows may vary from about 2 to 6.
In Fig. 10 there is shown a device 100 with a segmental configuration having a series of truncated cone-shaped segments 102 interconnected along the length of the device 100 and with dome shaped end portions 104. In one embodiment, the device 100 had a core diameter "a" of 1.4 mm and with the length "c" of each segment 102 being about 1 mm. In this embodiment, the overall base width "f" of each segment 102 was 1.7 mm and the overall length of the device 100 was 25 mm.
The device 110 of Fig. 11 also has a segmented configuration with a series of truncated cone-shaped segments 112 interconnected along the length of the device 110 and with dome-shaped end portions 114. In this embodiment, however, the device 110 is formed with mirror image segmental portions 116 and 118 so that the left one-half portion 116 of the device 110 is a mirror image of the right one-half portion 118. In one embodiment, the device 110 had a core diameter "a" of 1.4 mm and with the length "c" of each segment 112 being about 1 mm. In this embodiment, the overall base width "f" of each segment 112 was 1.7 mm and the overall length of the device 110 was 25 mm.
The device 111 of Fig. 12 has a braided design in which a series of braided segments 113 are interconnected along the length of the device 111 and with dome shaped end portions 115. In one embodiment, the device 111 had a core diameter "a" of 1.4 mm and with the length "c" of each segment 113 being 1 mm. In this embodiment, the braided segments 113 extended outwardly from the core by a distance "b" of 0.15 mm and the overall length of the device 111 was 25 mm.
In a further embodiment of the invention, the ocular insert device of the present invention may be formed with a polygonal shape in cross section, with the polygon having, for example, five or six equal sides. Such polygonal shape may be employed as the central core with any of the configurations shown in Figs. 7 through 12.
The drug loaded OCUFIT SR device can be formed by any of various processes such as extrusion molding, injection molding, transfer molding or compression molding.
In carrying out the extrusion molding process, polymer material is blended with drug at ratios of drug up to 40% by weight on a cooled two roll mill and then fed into a screw drive extruder. By the action of the single flight screw with diminishing pitch and a length to diameter ratio of about 12:1 to 10:1, material is continuously forced out through a coin or plate die (port) with openings conforming to the shape and dimensions of the subject device (i.e. circular) . For designs involving tube configurations, a mandrel held in place by a spider flange is positioned prior to the die. The continuous noodle is pulled via conveyer belt through a heated horizontal or vertical chamber (315 to 425 degrees C) to achieve vulcanization of the material. The final OCUFIT SR device is made by a cutting apparatus where the rods are cut to size. Additional modifications such as polishing the ends of the device can be accomplished.
In carrying out the transfer molding process, the blend of polymer material and drug is placed into a heated transfer press with an aluminum or stainless steel mold containing impressions of the proper shape and size. The material is forced into the mold at between 200 and 4000 psi. The mold itself is kept under 10 tons of clamp pressure. The mold is kept heated and under pressure at any of the following conditions:
4 - 10 minutes 135 degrees C
15 minutes 100 degrees C
30 minutes 75 degrees C 2 hours 55 degrees C
5 hours 40 degrees C
24 hours Ambient temperature (25°C)
The mold is cooled, separated and the formed OCUFIT SR devices are then removed.
In one embodiment, silicone rubbers/elastomers are employed as the material from which the device is formed. The silicone rubbers/elastomers are prepared as follows:
Silicone rubber prepared using dimethylsiloxane polymer or dimethyl and methylvinyl siloxane copolymers, reinforcing silica, platinum catalyst, inhibitor and siloxane crosslinker and other vulcanizing agents such as organic peroxides is either hand mixed, mixed on a two roll mill, or injection molded together with micronized drug (predominantly 10 micron particles or less) . Drug is loaded into the polymer mixture at levels up to 40 weight percent of the total weight together with any other necessary excipients or release modifiers such as glycerin or sorbitol. Entrapped air within the mixture is removed by exposure to a vacuum of about 28 inches of mercury (94.8 kPa) for approximately 30 minutes. Drug is solidified within the polymer matrix by curing (vulcanizing) the mixture while being molded into the desired shape.
The device may also be formed of bioerodible polymers prepared as follows:
Solid mixtures of bioerodible polymers (Polyhydroxyacids such as polylactic acid and polyglycolic acid, and polyhydroxybutyrate; Polyesters and polyorthoesters including cyclic ortho-esters with diols or diketeneacetals or diacids with diols or polyols; Polyanhydrides made from one or more of the following: p-carboxyphenoxy propane, p-carboxyphenoxy hexane, sebacic acid, dodecanedioic acid, 1,4- phenylenedipropionic acid, isophthalic acid, polypropylene fumarate and polypropylene maleate; Polypeptides; and Polycyanoacrylates) can be admixed with up to about 60% by weight of drug. The material can be compressed in aluminum or stainless steel molds situated in a Carver hydraulic press at 12 tons of pressure for at least 15 minutes at 100 degrees C.
As a further example, the device may be formed of methacrylate hydrogels prepared as follows:
Hydrogels loaded with drug can be constructed from crosslinked methacrylate polymers which include compositions containing one or more of the following: 2- hydroxyethyl methacrylate (HEMA) , ethylene glycol dimethacrylate, polymethylmethacrylate , methylmethacrylate, glycol monomethacrylate, ethylene monomethacrylates, glycol dimethacrylates, vinylpyrrolidone, methacrylic acid, divinylbenzene, and alkyldiol methacrylates, acrylamide, methylene bis acrylamide.
Various crosslinking percentages can be achieved by altering the ratios of the copolymers. For example a 40:1 weight ratio of acrylamide to methylene bis acrylamide produces a 2.5% crosslinking. A buffered solution (pH 7-9) of the copolymers is made containing the desired crosslinking ratio. The final total polymer percentage can be varied from 1 to 25%. Drug is admixed into this solution. Suitable crosslinking free radical generator and catalyst (such as ammonium persulfate and tetra methyl ethylene diamine) is added. The mixture is poured into an appropriate mold with the desired shape. Polymerization occurs within 30 minutes.
These embodiments of the invention may employ the ophthalmic drugs and pharmaceutically acceptable carriers as previously described.
The following are specific examples which were carried out in accordance with the present invention. Example 1
One part of silastic MDX4-4210 curing agent (Dow Corning Corp, Midland, MI) was mixed with 10 parts of MDX4-4210 Silastic base elastomer (Dow Corning Corp, Midland, MI) . The material was placed under vacuum of about 28 inches of mercury (94.8 kPa) for 30 minutes. Material was then transfered into a cylinder situated in a transfer press. The material was then forced into a 12 cavity aluminum mold heated to 135 degrees C which contained impressions of the ribbed device design and forced into the mold at a transfer pressure of 400 psi (2757.9 kPa) for 3.5 minutes. The mold itself is kept under 10 tons of clamp pressure. The mold was cooled, separated and the formed devices were removed. The devices were cleaned by soaking in isopropyl alcohol for approximately 5 minutes and allowed to air dry. Example 2
One part of silastic MDX4-4210 curing agent (Dow Corning Corp, Midland, MI) was mixed with 10 parts of MDX4-4210 silastic base elastomer (Dow Corning Corp, Midland, MI) . Oxytetracycline hydrochloride (Sigma Chemical Co., St. Louis) in the amount of 1% by weight of the total mixture was thoroughly blended in with care taken to minimize entrapment of air. The material was placed under vacuum of about 28 inches of mercury (94.8 kPa) for 30 minutes. Material was then transfered into a cylinder situated in a transfer press. The material was then forced into a 12 cavity aluminum mold heated to 135 degrees C which contained impressions of the ribbed device design and forced into the mold at a transfer pressure of 400 psi (2757.9 kPa) . The mold itself was kept under 10 tons of clamp pressure for 3.5 minutes. The mold was cooled, separated and the formed devices were removed.
Example 3
One part of Silastic MDX4-4210 curing agent (Dow Corning Corp, Midland, MI) was mixed with 10 parts of MDX4-4210 Silastic base elastomer (Dow Corning Corp, Midland, MI) . Oxytetracycline hydrochloride (Sigma Chemical Co., St. Louis) in the amount of 20% by weight of the total mixture was thoroughly blended in with care taken to minimize entrapment of air. The material was placed under vacuum of about 28 inches of mercury (94.8 kPa) for 30 minutes. Material was then transfered into a cylinder situated in a transfer press. The material was then forced into a 12 cavity aluminum mold heated to 121 degrees C which contained impressions of the ribbed device design and forced into the mold at a transfer pressure of 800 psi (5515.8 kPa) . The mold itself was kept under 10 tons of clamp pressure for 3.25 minutes. The mold was cooled, separated and the formed devices were removed.
Example 4
Silastic medical grade ETR elastomer Q7-4720 (Dow Corning Corp, Midland, MI) was prepared by first individually softening Part B and Part A of the elastomer on a cooled two-roll mill. The two components were then blended together in a 1:1 ratio on the two-roll mill. Material was then transfered into a cylinder situated in a transfer press. The material was then forced into a 12 cavity aluminum mold heated to 121 degrees C at a transfer pressure of 800 psi (5515.8 kPa) . The mold itself was kept under 10 tons of clamp pressure for 3.25 minutes. The mold was cooled, separated and the formed devices were removed.
Example 5
Medical grade liquid silicone rubber Silastic Q7- 4840 A/B (Dow Corning Corp, Midland, MI) was prepared by mixing equal portions of the A and B components. A vacuum of 29-29 inches of mercury (98.2 kPa) was applied to the mixture for 30 minutes to deair the material. The material was compression molded in an aluminum mold in a carver press for 15 minutes at 100 degrees C under 12 tons of pressure. The mold was cooled, separated, and the devices removed. The devices were cleaned by soaking in isopropyl alcohol for approximately 5 minutes and allowed to air dry.
Example 6
Silastic medical grade ETR elastomer LSR 76000 (Dow Corning Corp. , Midland, MI) was prepared by first individually softening Part B and Part A of the elastomer on a cooled two-roll mill. The two components were then blended together in a 1:1 ratio on the two-roll mill. Oxytetracycline hydrochloride with or without USP grade dextrose premixed in various ratios was added incrementally into the blend to assure homogeneous distribution. Material was then transferred into a cylinder situated in a transfer press. The material was then forced into a 12 cavity aluminum mold heated to 121°C at a transfer pressure of 800 psi (5515.8 kPa) . The mold itself was kept under 10 tons of clamp pressure for 3.25 minutes. The mold was cooled, separated and the formed devices were removed.
Example 7 For control devices not containing any protrusion beyond the core, simple cylindrical rods were prepared as in Example 1 except using a mold with impressions of a simple rod shape.
Example 8
A study was carried out in which the device of the present invention was inserted into the eyes of human patients with either no disease or suffering from conjunctivitis, corneal disease, anterior uveitis, trachoma, or episcleritis. Initially, one drop of anesthetic was placed on the eye. After 2 minutes a small amount of eye ointment (such as Neosporin, Burroughs Wellcome, Research Triangle Park, NC) was applied to the lower fornix. The subject was instructed to blink several times. After two to three minutes either the ribbed device of Example 1 or non-modified rod controls of Examples 2, 5 or 7 were secured in the middle with a clean blunt forceps. With the subject looking down, the upper lid was separated from the globe using the thumb of the free hand. With the subject continuing to look down, the tip of the forceps and the device was gently pushed under the lid toward the fornix about 6-7 mm inward, making sure the device was centered in the fornix. The device was released from the forceps. With a tip of the finger the device was maneuvered into the deep fornix. The subject was instructed to move the eye up and down 3 times while holding the tip of the finger over the lid near the fornix. Results are shown below in Table 1.
TABLE 1 Device Type Days Retained Number (percent) of in Fornix patients retaining device
Control devices 0-6 36 (40.5%) without ribbing (from Examples 4,5,and 7)
7-28 53 (59.5%ϊ TOTAL 89 (100%)
Ribbed devices 0-6 3 (20%) (from Example 1)
7-28 12 (80%
TOTAL 15 (100%)
Conclusion: In these experiments ribbed OCUFIT SR devices minimized lateral movement and are better retained in the fornix (80%) than rods without ribbing (59.5%) in ocular disease patients for periods of 7-28 days.
Additional work was carried out to study the retainability of a ribbed OCUFIT SR device measuring 25 mm in length x 1.4 mm (core diameter) and 1.7 mm
(protrusion diameter) for a period of up to four weeks in the normal eyes of human volunteers. These were patients whose eyes were free of active disease as compared to the study of Example 8 above in which most of the patients were suffering from eye disease at the time of the test.
The configuration of the ribbed OCUFIT SR device was as shown in Fig. 7 of the drawings but with five ribs.
The material employed was a solid silastic based material
MDX4-4210, a medical grade elastomer. No drug was incorporated into the OCUFIT SR device and the ends of the device were rounded.
This additional study was carried out in the eyes of human volunteers, rather than experimental animals since the size and depths of the upper or lower fornix of experimental animals are different from the human eye. In some animals, the presence and movement of nictitating membrane can dislodge the OCUFIT SR device.
The method used in this study was as follows: The volunteer was asked to sit down, hold his/her chin slightly up and to look down continuously throughout the exercise.
The eye was anaesthetized by a drop of Benoxenate
(oxybuprocaine) hydrochloride o.4% W/V (Smith & Nephew).
The upper lid was separated from the globe by about 4 to 5 millimeters by holding lashes and gently pulling the lid backward and upward. The OCUFIT SR device held in the forceps was centrally located at a midpoint between the nasal and temporal canthus and was pushed under the upper lid inward about 6 to 7 mm. The tip of a finger was positioned in the middle of the eyelid just above the end of the forceps before the OCUFIT SR device was released and forceps removed. The device was released and the ends of the device were allowed to orient toward the respective canthus. With the tip of a finger the OCUFIT SR device was gently pushed upward and toward the deep fornix. The maneuver was repeated twice more in each corner (canthus) . The volunteer was asked to move the eye downward and upward three times. The volunteer was advised:
(a) If he/she feels that the end of the OCUFIT SR device was near the inner or outer corner (nasal or temporal canthus) of the eye or feels irritation, he/she can push the OCUFIT SR device back to the middle of the fornix by closing the eye and looking down, then, with the tip of a finger gently press the corner of the eye.
(b) Repeat maneuver explained above once in the morning after waking up and once in the evening before sleeping.
(c) Avoid rubbing the eyes.
(d) It is not possible to visualize the OCUFIT SR device in the deep fornix but he/she may be aware of sensation in a corner of the eye, relieved by prodding the upper part of the lid with a finger tip after closing the eye.
After taking a history, the eyes were examined by a slit lamp. The clinical signs of the conjunctiva, cornea and anterior uvea were recorded on a specially designed proforma.
The duration of retention was planned for four weeks.
Alternatively, a mechanical insertion device may be employed for insertion of the device of the present invention.
No additional topical or systemic treatment was given to any of the volunteers. The volunteers were asked to report to the investigator if the OCUFIT SR device was rejected from the eye.
The results of the retention study are shown in Table 2. TABLE 2
RETENTION OF RIBBED OCUFIT SR DEVICE IN THE EYE OF VOLUNTEERS
Days of Retention Sub. Initial Age Sex Eye 1 5 11 24 28 32+ OCUFIT No. SR
1 MMR 29 F N 11 Rej .
MMR** 29 F N 32 Rem.
2 AH 24 F N —3 Rej .
3 SD 63 M N 64 -Rem.
4 MH 25 M N 5 Rej .
5 JH 22 M N 28 Rem.
6 AG 23 M N 28 Rem.
7 MG 24 M N 24 Rej .
8 SH 22 M N 28 Rem.
9 RMW 43 M N 5 Rej .
N = Normal ** = Second attempt Rej. - Rejected Rem. - Removed
Nine volunteers with normal eyes were included. The age and gender of the volunteers are presented in Table 2.
In eight volunteers, the OCUFIT SR device was inserted once and in one volunteer (MMR) it was inserted twice.
The OCUFIT SR device was inserted in the upper fornix of the left eye in 8 volunteers and in the upper fornix of the right eye in one volunteer (RMW) .
The period of retention for each volunteer is shown in Table 2. In six volunteers (67%), the OCUFIT SR device was retained for 24 days or more. Of these, five retained the device for 28 days or longer before it was removed and in one volunteer (case 7, MG) the OCUFIT SR device came out on day 24 for no apparent reason. In one volunteer (case 1, MMR) the first OCUFIT SR device came out on day 11 after vigorous physical exercise. The second OCUFIT SR device in this volunteer retained well for 32 days before it was removed. In three volunteers (cases 2,4 and 9) the OCUFIT SR device retained between 3 and 5 days respectively. In cases 2 and 4, OCUFIT SR device was rejected after rubbing of the eye and in case 9, it came out from the outer corner of the eye for no apparent reason.
In Figs. 13 and 14, there are provided various graphs showing drug release data in accordance with the present invention. In Fig. 13 a Q7-4735 elastomer was employed and the desired or theoretical release rate for efficacy is shown as well as results obtained when the device was loaded with oxytetracycline in an amount of 10% of the weight of the unloaded device.
The data in Fig. 14 is for various amounts of loading of oxytetracycline in a device formed of the MDX4-4210 elastomer, with Fig. 14 showing results over a 24 hour period.
Fig. 15 shows a graph of drug release data in accordance with the present invention, in which dextrose is employed as a release modifier. As shown in the graph, the solids percentage is maintained at 30% and the amount of dextrose is varied between 0 and 15%, as shown in the different curves. By adding dextrose, more pores or pathways are created for drug diffusion. These drugs are employed with suitable carriers as previously discussed.
In Fig. 16 there is shown a graph of the swelling rate of a particular elastomer employed in a device of the present invention. Swelling is caused by the migration of water into the polymer, dissolving the drug and causing the polymer to swell due to an osmotic effect as water forces the polymer outwardly. Such swelling can be desirable inasmuch as a device of the present invention may lock into place as it grows in size. It has been found that the silicone materials are particularly prone to swell in this manner. As indicated by the graph, it is within the scope of the invention to select the initial dimensions of a device and, by selecting the proper combination of solid materials, e.g., oxytetracycline and dextrose, to provide for the desired final dimensions of the device after swelling. In Fig. 16 there are shown the measurements obtained with regard to swelling of a device of the present invention which has been loaded with oxytetracycline and dextrose. At large drug loads, the device can swell so that both length and diameter are increased significantly. In view of this tendency to swell when drug has been incorporated, there are several possible approaches: (1) start with a small rod that is initially inserted; (2) adjust the ratio of drug to release modifiers which will affect the rate of water diffusion into the rod; and (3) adjust the amount of platinum catalyst to facilitate more complete cross-linking of the polymeric rod material which reduces the amount of swelling.
The data in Table 3 show physical properties, including tensile strength and % elongation for a device of the present invention prepared in various formulations with various amounts of oxytetracycline, glycerine and polyethlene glycol.
TABLE 3
PHYSICAL PROPERTIES
FORMULATION TENSILE ELONGATION (PSI) (%)
30% OTC 287.2 (1980.2 kPa) 622.8
10% OTC; 5% GLY 382.5 (2637.2 kPa) 604.6 30% OTC; 10% PEG 8000 183.5 (1265.2 kPa) 534.6
While the ocular insert of the present invention has been described herein as particularly well suited for treatment of humans, it is also within the scope of the invention to employ the present invention in the treatment of other animals such as cows and horses for diseases such as pink eye and the like.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. A flexible ocular insert device adapted for the controlled sustained release of an ophthalmic drug upon insertion into the upper or lower fornix of the eye, said device comprising an elongated body of a polymeric material in the form of a rod or tube containing a pharmaceutically active ingredient and with at least two anchoring protrusions extending radially outwardly from said body, said device having a length of at least 8 mm and a diameter including protrusions not exceeding 1.9 mm, wherein said device is sufficiently flexible to allow it to bend along the curvature of the eye within the upper or lower fornix upon being positioned so that the longitudinal axis of said device is generally parallel to the transverse diameter of the eyeball, said device being of a size and configuration such that, upon insertion into the upper or lower fornix, the device does not extend onto any visible portion of the eyeball, said device being independent of movement of the eye and remaining out of the field of vision so as to be well retained in place and imperceptible by a patient over a prolonged period of use, said protrusions acting to minimize lateral movement of the device within the fornix, whereby the device when inserted into the upper or lower fornix can be retained therein for more than seven days.
2. A device according to claim 1 wherein the protrusions extend outwardly a distance such that the overall diameter of the device including the protrusions is approximately 15 to 30 percent greater than the diameter of the body of said device.
3. A device according to claim 1 wherein the length of the device is from 8 to 25 mm for use in the lower fornix to suit the eyes of different sizes such as infants, children and adults.
4. A device according to claim 1 wherein the length of the device is from 8 to 35 mm for use in the upper fornix to suit the eyes of different sizes such as infants, children and adults.
5. A device according to claim 1 wherein the diameter of the device including protrusions is from 0.5 to 1.9 mm to suit the eyes of different sizes such as infants, children and adults.
6. A device according to claim 1 wherein the body is tubular and the mechanism of drug release is by diffusion through an outer wall (120) of the device.
7. A device according to claim 1 wherein the body is tubular and the mechanism of drug release is by osmosis.
8. A device according to claim 1 wherein the body is in the shape of a rod and the mechanism of drug release is bioerosion.
9. A device according to claim 1 wherein the body is a non-erodible rod and the mechanism of drug release is by diffusion including possible drug dissolution.
10. A device according to claim 1 wherein said device has a cylindrical shaped body.
11. A device according to claim 1 wherein said device has a polygonal shaped body.
12. A device according to claim 1 wherein said protrusions are evenly spaced relative to the length of the device.
13. A device according to claim 1 wherein said protrusions are positioned so as to be symmetrical with respect to said body.
14. A device according to claim 1 wherein said protrusions are toroidal or doughnut shaped around the body to provide a ribbed configuration (76) .
15. A device according to claim 1 wherein said protrusions are in the form of a winding such as a screw thread (86) around the body.
16. A device according to claim 1 wherein said protrusions are in the shape of hemispherical dimples or bumps (92) .
17. A device according to claim 1 wherein said protrusions are in the form of a series of truncated cone-shaped segments (102) wherein the longitudinal axis of said cone-shaped segments (102) is coaxial with the longitudinal axis of said body.
18. A device according to claim 17 wherein said truncated cone-shaped segments (102) are arranged so that a portion (116) of said device is a mirror image of another portion (118) of said device.
19. A device according to claim 1 wherein said protrusions are in the form of winding braid segments (113).
20. A device according to claim 1 wherein the polymeric material is a silicone elastomer.
21. A device according to claim 1 wherein the polymeric material is made of hydrogel components.
22. A device according to claim 1 wherein the polymeric material is a methacrylate or hydroxymethacrylate based material.
23. A method for the controlled sustained release of an ophthalmic drug into the eye over a period of time which comprises:
(a) inserting an elongated device having a body of a polymeric material in the form of a rod or tube containing an ophthalmic drug into the upper or lower fornix so as to anchor said device into position therein, with at least two anchoring protrusions extending radially outwardly from said body, said device having a length of at least 8 mm and a diameter including protrusions which does not exceed 1.9 mm, wherein said device is sufficiently flexible to allow it to bend along the curvature of the eye within the upper or lower fornix upon being positioned so that the longitudinal axis of said device is generally parallel to the transverse diameter of the eyeball, said device being of a size and configuration such that, upon insertion into the upper or lower fornix, the device does not extend onto any visible portion of the eyeball, said device being independent of movement of the eye and remaining out of the field of vision so as to be well retained in place and imperceptible by a patient over a prolonged period of use, with said protrusions acting to minimize lateral movement of the device within the fornix; and
(b) allowing said device to remain in the upper or lower fornix for drug release during said period of time, whereby the device when inserted into the upper or lower fornix can be retained therein for more than seven days.
24. The method of claim 23 wherein the protrusions extend outwardly a distance such that the overall diameter of the device including the protrusions is approximately 15 to 30 percent greater than the diameter of the body of said device.
25. The method of claim 23 wherein said protrusions are evenly spaced relative to the length of the device.
26. The method of claim 23 wherein said protrusions are positioned so as to be symmetrical with respect to said body.
27. The method of claim 23 wherein said protrusions are toroidal or doughnut shaped around the body to provide a ribbed configuration (76) .
28. The method of claim 23 wherein said protrusions are in the form of a winding such as a screw thread (86) around the body.
29. The method of claim 23 wherein said protrusions are in the shape of hemispherical dimples or bumps (92) .
30. The method of claim 23 wherein said protrusions are in the form of a series of truncated cone-shaped segments (102) wherein the longitudinal axis of said cone-shaped segments (102) is coaxial with the longitudinal axis of said body.
31. The method of claim 23 wherein said truncated cone-shaped segments (102) are arranged so that a portion (116) of said device is a mirror image of another portion (118) of said device.
32. The method of claim 23 wherein said protrusions are in the form of winding braid segments (113) .
33. The method of claim 23 wherein the length of the device is from 8 to 25 mm for use in the lower fornix to suit the eyes of different sizes such as infants, children and adults.
34. The method of claim 23 wherein the length of the device is from 8 to 35 mm for use in the upper fornix to suit the eyes of different sizes such as infants, children and adults.
35. The method of claim 23 wherein the diameter of the device including protrusions is from 0.5 to 1.9 mm to suit the eyes of different sizes such as infants, children and adults.
36. The method of claim 23 wherein the body is tubular and the mechanism of drug release is by diffusion through an outer wall of the device.
37. The method of claim 23 wherein the body is tubular and the mechanism of drug release is by osmosis.
38. The method of claim 23 wherein the body is in the shape of a rod and the mechanism of drug release is bioerosion.
39. The method of claim 23 wherein the body is a non-erodible rod and the mechanism of drug release is by diffusion including possible drug dissolution.
40. The method of claim 23 wherein said device has a cylindrical shaped body.
41. The method of claim 23 wherein said device has a polygonal shaped body.
42. The method of claim 23 wherein insertion of the device is accomplished by (a) securing the device centrally with respect to the nasal and temporal canthus, (b) gently inserting the device under the lid at a midpoint between the nasal and temporal canthus and from 6 to 7 mm inward while the lid has been separated from the globe by about 4 to 5 mm, (c) releasing the device and allowing the ends to orient toward the respective canthus, and (d) using the tip of the finger on the surface of the lid to manipulate the device into final position in the deep fornix.
43. The method of claim 23 which further includes selecting as the polymeric material for the body a material which is subject to swelling in a liquid environment.
44. The method of claim 43 wherein a device is employed having dimensions which initially are smaller than the desired final dimensions, so that the device is assisted in locking into place as the device increases in size after insertion into the fornix.
45. The method of claim 43 which includes the further step of adjusting the ratio of drug to release modifier during manufacture of said device to affect the rate of liquid diffusion into the device.
46. The method of claim 43 which includes the further step of adjusting the amount of catalyst during manufacture of said device to facilitate the amount of cross-linking and thus the amount of swelling of the polymeric rod material.
47. The method of claim 43 wherein the device increases in size in both length and diameter.
48. A flexible ocular insert device adapted for the controlled sustained release of an ophthalmic drug upon insertion into the upper or lower fornix of the eye, said device comprising an elongated body of a polymeric material in the form of a rod or tube containing a pharmaceutically active ingredient, said polymeric material being a material which is subject to swelling in a liquid environment.
49. The ocular insert device of claim 48 wherein said polymeric material is a silicone-containing material.
50. The ocular insert device of claim 48 wherein said polymeric material is liquid silicone rubber.
51. A method for the controlled sustained release of an ophthalmic drug into the eye over a period of time which comprises:
(a) inserting an elongated device having a body of a polymeric material in the form of a rod or tube containing an ophthalmic drug into the upper or lower fornix so as to anchor said device into position therein, wherein said polymeric material is a material which is subject to swelling in a liquid environment; and (b) allowing said device to remain in the upper or lower fornix for drug release during said period of time.
52. The method of claim 51 wherein a device is employed having dimensions which initially are smaller than the desired final dimensions, so that the device is assisted in locking into place as the device increases in size after insertion into the fornix.
53. The method of claim 51 which includes the further step of adjusting the ratio of drug to release modifier during manufacture of said device to affect the rate of liquid diffusion into the device.
54. The method of claim 51 which includes the further step of adjusting the amount of catalyst during manufacture of said device to facilitate the amount of cross-linking and thus the amount of swelling of the polymeric rod material.
55. The method of claim 51 wherein said polymeric material is a silicone-containing material.
56. The method of claim 51 wherein said polymeric material is liquid silicone rubber.
PCT/US1994/007136 1993-06-29 1994-06-20 Ocular insert with anchoring protrusions WO1995001764A2 (en)

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US08/083,303 1993-06-29
US08/083,303 US5322691A (en) 1986-10-02 1993-06-29 Ocular insert with anchoring protrusions

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001032140A1 (en) * 1999-11-04 2001-05-10 Btg Int Ltd Ocular insert
US9168222B2 (en) 2006-03-31 2015-10-27 Mati Therapeutics Inc. Nasolacrimal drainage system implants for drug therapy
US9610271B2 (en) 2011-08-29 2017-04-04 Mati Therapeutics Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
US9937073B2 (en) 2010-06-01 2018-04-10 Forsight Vision5, Inc. Ocular insert apparatus and methods
US9974685B2 (en) 2011-08-29 2018-05-22 Mati Therapeutics Drug delivery system and methods of treating open angle glaucoma and ocular hypertension
US10004636B2 (en) 2009-06-03 2018-06-26 Forsight Vision5, Inc. Anterior segment drug delivery
US10456293B2 (en) 2012-10-26 2019-10-29 Forsight Vision5, Inc. Ophthalmic system for sustained release of drug to eye
US10610407B2 (en) 2004-07-02 2020-04-07 Mati Therapeutics Inc. Treatment medium delivery device and methods for delivery of such treatment mediums to the eye using such delivery device
US11224602B2 (en) 2015-04-13 2022-01-18 Forsight Vision5, Inc. Ocular insert composition of a semi-crystalline or crystalline pharmaceutically active agent

Families Citing this family (126)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5989579A (en) * 1986-10-02 1999-11-23 Escalon Medical Corp. Ocular insert with anchoring protrusions
US5322691A (en) * 1986-10-02 1994-06-21 Sohrab Darougar Ocular insert with anchoring protrusions
US5817075A (en) * 1989-08-14 1998-10-06 Photogenesis, Inc. Method for preparation and transplantation of planar implants and surgical instrument therefor
US6514238B1 (en) * 1989-08-14 2003-02-04 Photogenesis, Inc. Method for preparation and transplantation of volute grafts and surgical instrument therefor
SG49267A1 (en) 1989-08-14 1998-05-18 Photogenesis Inc Surgical instrument and cell isolation and transplantation
US6045791A (en) * 1992-03-06 2000-04-04 Photogenesis, Inc. Retinal pigment epithelium transplantation
JP3720386B2 (en) * 1993-12-27 2005-11-24 住友製薬株式会社 Drug release controlled formulation
US5618274A (en) * 1994-04-08 1997-04-08 Rosenthal; Kenneth J. Method and device for deep pressurized topical, fornix applied "nerve block" anesthesia
US5868728A (en) * 1995-02-28 1999-02-09 Photogenesis, Inc. Medical linear actuator for surgical delivery, manipulation, and extraction
US5869079A (en) * 1995-06-02 1999-02-09 Oculex Pharmaceuticals, Inc. Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents
US20060280774A1 (en) * 1995-06-02 2006-12-14 Allergan, Inc. Compositions and methods for treating glaucoma
US6299895B1 (en) 1997-03-24 2001-10-09 Neurotech S.A. Device and method for treating ophthalmic diseases
EP0973499B1 (en) * 1997-03-31 2003-08-06 Alza Corporation Diffusional implantable delivery system
US6196993B1 (en) * 1998-04-20 2001-03-06 Eyelab Group, Llc Ophthalmic insert and method for sustained release of medication to the eye
EP1154691A4 (en) * 1999-01-05 2004-07-07 Massachusetts Eye & Ear Infirm Targeted transscleral controlled release drug delivery to the retina and choroid
US6416777B1 (en) 1999-10-21 2002-07-09 Alcon Universal Ltd. Ophthalmic drug delivery device
US7943162B2 (en) * 1999-10-21 2011-05-17 Alcon, Inc. Drug delivery device
ATE283013T1 (en) * 1999-10-21 2004-12-15 Alcon Inc MEDICATION DELIVERY DEVICE
EP1221918B1 (en) 1999-10-21 2005-03-16 Alcon Inc. Sub-tenon drug delivery
US6726918B1 (en) 2000-07-05 2004-04-27 Oculex Pharmaceuticals, Inc. Methods for treating inflammation-mediated conditions of the eye
ES2312456T3 (en) * 2000-08-30 2009-03-01 Johns Hopkins University DEVICES FOR INTRAOCULAR SUPPLY OF PHARMACOS.
DK1339438T3 (en) * 2000-11-29 2006-02-13 Allergan Inc Prevention of transplant rejection in the eye
US6713081B2 (en) * 2001-03-15 2004-03-30 The United States Of America As Represented By The Department Of Health And Human Services Ocular therapeutic agent delivery devices and methods for making and using such devices
US7563255B2 (en) 2001-05-03 2009-07-21 Massachusetts Eye And Ear Infirmary Implantable drug delivery device and use thereof
DE60239868D1 (en) 2001-06-12 2011-06-09 Univ Johns Hopkins Med RESERVOIR DEVICE FOR INTRAOCULAR DRUG DELIVERY
PL204644B1 (en) 2001-07-23 2010-01-29 Alcon Ophthalmic drug delivery device
JP4249611B2 (en) * 2001-07-23 2009-04-02 アルコン,インコーポレイティド Ophthalmic drug delivery device
EP1418864A4 (en) * 2001-08-03 2009-07-01 Research Technologies Glaucoma Method and intra sclera implant for treatment of glaucoma and presbyopia
GB2399020B (en) * 2002-02-14 2005-01-12 Photogenesis Inc Subretinal implantation device and surgical cannulas for use therewith
WO2003092665A2 (en) * 2002-05-02 2003-11-13 Massachusetts Eye And Ear Infirmary Ocular drug delivery systems and use thereof
CA2511217A1 (en) * 2002-12-20 2004-07-15 Chakshu Research, Inc. Ophthalmic formulation for the prevention and treatment of ocular conditions
US20050048099A1 (en) 2003-01-09 2005-03-03 Allergan, Inc. Ocular implant made by a double extrusion process
WO2004073551A2 (en) * 2003-02-18 2004-09-02 Massachusetts Eye And Ear Infirmary Transscleral drug delivery device and related methods
EP1633320A2 (en) * 2003-05-02 2006-03-15 SurModics, Inc. Implantable controlled release bioactive agent delivery device
US8246974B2 (en) * 2003-05-02 2012-08-21 Surmodics, Inc. Medical devices and methods for producing the same
MXPA05011517A (en) * 2003-07-10 2005-12-12 Alcon Inc Ophthalmic drug delivery device.
WO2005020907A2 (en) * 2003-08-26 2005-03-10 Vista Scientific Ocular drug delivery device
US7759472B2 (en) * 2003-08-27 2010-07-20 Ophthotech Corporation Combination therapy for the treatment of ocular neovascular disorders
US7585517B2 (en) * 2003-09-18 2009-09-08 Macusight, Inc. Transscleral delivery
US20050232972A1 (en) * 2004-04-15 2005-10-20 Steven Odrich Drug delivery via punctal plug
US20050244469A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Extended therapeutic effect ocular implant treatments
US20060024350A1 (en) * 2004-06-24 2006-02-02 Varner Signe E Biodegradable ocular devices, methods and systems
US20060110428A1 (en) * 2004-07-02 2006-05-25 Eugene Dejuan Methods and devices for the treatment of ocular conditions
PT1781264E (en) 2004-08-04 2013-10-16 Evonik Corp Methods for manufacturing delivery devices and devices thereof
US7722669B2 (en) * 2004-08-13 2010-05-25 Richard Foulkes Method and insert for modifying eye color
BRPI0519171A2 (en) * 2004-12-22 2008-12-30 Alcon Inc ophthalmic drug delivery device
WO2006086750A1 (en) * 2005-02-09 2006-08-17 Macusight, Inc. Liquid formulations for treatment of diseases or conditions
US8663639B2 (en) * 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
EP1868661A1 (en) * 2005-04-08 2007-12-26 SurModics, Inc. Sustained release implants for subretinal delivery
WO2007014327A2 (en) 2005-07-27 2007-02-01 University Of Florida Research Foundation, Inc. Small compounds that correct protein misfolding and uses thereof
ATE543914T1 (en) * 2005-09-01 2012-02-15 Bristol Myers Squibb Co BIOMARRKERS AND METHODS FOR DETERMINING SENSITIVITY TO VEGFR2 MODULATOR.
EP2329821B1 (en) 2005-11-29 2012-08-22 GlaxoSmithKline LLC Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema
US20070178138A1 (en) * 2006-02-01 2007-08-02 Allergan, Inc. Biodegradable non-opthalmic implants and related methods
CA2635797C (en) 2006-02-09 2015-03-31 Macusight, Inc. Stable formulations, and methods of their preparation and use
KR101520408B1 (en) 2006-03-23 2015-05-14 산텐 세이야꾸 가부시키가이샤 Formulations and methods for vascular permeability-related diseases or conditions
US20070298073A1 (en) * 2006-06-23 2007-12-27 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods
US8802128B2 (en) * 2006-06-23 2014-08-12 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods
US8828419B2 (en) * 2006-10-06 2014-09-09 Cordis Corporation Bioabsorbable device having encapsulated additives for accelerating degradation
US8394488B2 (en) * 2006-10-06 2013-03-12 Cordis Corporation Bioabsorbable device having composite structure for accelerating degradation
WO2008083118A1 (en) * 2006-12-26 2008-07-10 Qlt Plug Delivery, Inc. Drug delivery implants for inhibition of optical defects
US20080265343A1 (en) * 2007-04-26 2008-10-30 International Business Machines Corporation Field effect transistor with inverted t shaped gate electrode and methods for fabrication thereof
CA2698574A1 (en) * 2007-09-07 2009-03-19 Qlt Plug Delivery, Inc. Insertion and extraction tools for lacrimal implants
JP5524841B2 (en) * 2007-09-07 2014-06-18 キュー エル ティー インク. Lacrimal implant and related methods
EP2205193A2 (en) 2007-09-07 2010-07-14 QLT Plug Delivery, Inc. Lacrimal implant detection
AU2008300013A1 (en) 2007-09-07 2009-03-19 Qlt Inc. Drug cores for sustained release of therapeutic agents
TWI451862B (en) * 2007-10-09 2014-09-11 Alcon Res Ltd Thermal coefficient driven drug pellet size for ophthalmic injection
TWI498136B (en) * 2007-10-09 2015-09-01 Alcon Res Ltd An injection device for delivering a rate and temperature-dependent substance into the eye and method of preparing the same
US8728528B2 (en) 2007-12-20 2014-05-20 Evonik Corporation Process for preparing microparticles having a low residual solvent volume
MX2010008998A (en) * 2008-02-18 2010-11-26 Qlt Plug Delivery Inc Lacrimal implants and related methods.
CN104623741A (en) 2008-04-30 2015-05-20 马缇医疗股份有限公司 Composite lacrimal insert and related methods
NZ588938A (en) * 2008-05-09 2013-03-28 Mati Therapeutics Inc Sustained release delivery of active agents to treat glaucoma and ocular hypertension
WO2010062394A2 (en) * 2008-11-26 2010-06-03 Surmodics, Inc. Implantable ocular drug delivery device and methods
CN102365109B (en) 2009-01-29 2015-06-03 弗赛特影像4股份有限公司 Posterior segment drug delivery
US8623395B2 (en) 2010-01-29 2014-01-07 Forsight Vision4, Inc. Implantable therapeutic device
AU2010215745A1 (en) * 2009-02-23 2011-09-01 Qlt Inc. Lacrimal implants and related methods
US20100226962A1 (en) * 2009-03-03 2010-09-09 Rodstrom Theron R Peri-corneal drug delivery device
US8372036B2 (en) 2009-05-06 2013-02-12 Alcon Research, Ltd. Multi-layer heat assembly for a drug delivery device
EP4289416A3 (en) * 2009-05-18 2024-01-03 Dose Medical Corporation Drug eluting ocular implant
IN2012DN00352A (en) 2009-06-16 2015-08-21 Bikam Pharmaceuticals Inc
RU2545865C2 (en) * 2009-09-22 2015-04-10 Евоник Корпорейшн Implanted devices with various versions of biologically active ingredient loading
WO2011039648A1 (en) 2009-09-30 2011-04-07 Glaxo Wellcome Manufacturing Pte Ltd. Methods of administration and treatment
WO2011044216A1 (en) * 2009-10-08 2011-04-14 Neurotech Usa, Inc. Use of pedf in an encapsulated cell-based delivery system
US8177747B2 (en) 2009-12-22 2012-05-15 Alcon Research, Ltd. Method and apparatus for drug delivery
US8469934B2 (en) * 2010-01-27 2013-06-25 Alcon Research, Ltd. Pulsatile peri-corneal drug delivery device
PL2600930T3 (en) 2010-08-05 2021-09-06 Forsight Vision4, Inc. Injector apparatus for drug delivery
US9492315B2 (en) 2010-08-05 2016-11-15 Forsight Vision4, Inc. Implantable therapeutic device
WO2012019139A1 (en) 2010-08-05 2012-02-09 Forsight Vision4, Inc. Combined drug delivery methods and apparatus
US8961501B2 (en) 2010-09-17 2015-02-24 Incept, Llc Method for applying flowable hydrogels to a cornea
AU2011329656B2 (en) 2010-11-19 2017-01-05 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US20120157938A1 (en) * 2010-12-16 2012-06-21 Tokarski Jason M Punctal plug with drug core retention features
US9133082B2 (en) 2011-06-14 2015-09-15 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
EP2726016B1 (en) 2011-06-28 2023-07-19 ForSight Vision4, Inc. An apparatus for collecting a sample of fluid from a reservoir chamber of a therapeutic device for the eye
EP2739252A4 (en) 2011-08-05 2015-08-12 Forsight Vision4 Inc Small molecule delivery with implantable therapeutic device
US9102105B2 (en) 2011-09-13 2015-08-11 Vista Scientific Llc Method for forming an ocular drug delivery device
US10226417B2 (en) 2011-09-16 2019-03-12 Peter Jarrett Drug delivery systems and applications
PL2755600T3 (en) 2011-09-16 2021-09-20 Forsight Vision4, Inc. Fluid exchange apparatus
EP2768307B1 (en) 2011-10-19 2020-03-18 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
AU2012346214B2 (en) 2011-11-30 2017-09-14 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
WO2013081642A1 (en) 2011-12-01 2013-06-06 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
EP3613413A1 (en) 2011-12-05 2020-02-26 Incept, LLC Medical organogel processes and compositions
US10010448B2 (en) 2012-02-03 2018-07-03 Forsight Vision4, Inc. Insertion and removal methods and apparatus for therapeutic devices
US9827401B2 (en) 2012-06-01 2017-11-28 Surmodics, Inc. Apparatus and methods for coating medical devices
MX351261B (en) 2012-06-01 2017-10-06 Surmodics Inc Apparatus and method for coating balloon catheters.
MX368730B (en) 2013-02-18 2019-10-14 Vegenics Pty Ltd Ligand binding molecules and uses thereof.
US9968603B2 (en) 2013-03-14 2018-05-15 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
WO2014160884A1 (en) 2013-03-28 2014-10-02 Forsight Vision4, Inc. Ophthalmic implant for delivering therapeutic substances
JP6340673B2 (en) 2013-05-02 2018-06-13 レティナ ファウンデーション オブ ザ サウスウエストRetina Foundation Of The Southwest Double-layered ocular implant
BR112016000546A2 (en) 2013-07-12 2017-11-21 Ophthotech Corp methods to treat or prevent eye conditions
ES2803102T3 (en) 2014-07-15 2021-01-22 Forsight Vision4 Inc Eye implant delivery device
CN107106551A (en) 2014-08-08 2017-08-29 弗赛特影像4股份有限公司 The stabilization of receptor tyrosine kinase inhibitors and solvable preparation and its preparation method
JP5643461B1 (en) * 2014-08-28 2014-12-17 株式会社ユニバーサルビュー Eyelid interior tools
JP5671183B1 (en) * 2014-08-28 2015-02-18 株式会社ユニバーサルビュー Eyelid interior tools
JP5643460B1 (en) * 2014-08-28 2014-12-17 株式会社ユニバーサルビュー Eyelid interior tools
WO2016031093A1 (en) * 2014-08-28 2016-03-03 株式会社ユニバーサルビュー Ocular insert device
CA2967330A1 (en) 2014-11-10 2016-05-19 Forsight Vision4, Inc. Expandable drug delivery devices and methods of use
WO2016187426A1 (en) 2015-05-19 2016-11-24 Amorphex Therapeutics Llc A device that delivers a sustained low-dose of a myopia-suppressing drug
AU2016355345A1 (en) 2015-11-20 2018-05-31 Forsight Vision4, Inc. Porous structures for extended release drug delivery devices
CN109195556B (en) 2016-04-05 2021-03-26 弗赛特影像4股份有限公司 Implantable ocular drug delivery device
US10383764B2 (en) * 2016-10-31 2019-08-20 Ebrahim Elahi Eyelid implant device
CA3082891A1 (en) 2017-11-21 2019-05-31 Forsight Vision4, Inc. Fluid exchange apparatus for expandable port delivery system and methods of use
US20200268554A1 (en) * 2018-05-12 2020-08-27 Goldenbiotech, Llc Self-Retaining Implantable Drug Delivery Device
US11628466B2 (en) 2018-11-29 2023-04-18 Surmodics, Inc. Apparatus and methods for coating medical devices
US11819590B2 (en) 2019-05-13 2023-11-21 Surmodics, Inc. Apparatus and methods for coating medical devices
US20210169690A1 (en) * 2019-12-10 2021-06-10 Goldenbiotech, Llc Self-Retaining Implantable Drug Delivery Device
EP4337143A1 (en) * 2021-05-14 2024-03-20 Glaukos Corporation Materials and methods for punctal plugs
WO2023073706A1 (en) * 2021-10-27 2023-05-04 Avisi Ltd. Ophthalmic device

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3828777A (en) * 1971-11-08 1974-08-13 Alza Corp Microporous ocular device
US4730013A (en) * 1981-10-08 1988-03-08 Merck & Co., Inc. Biosoluble ocular insert
US5229128A (en) * 1986-06-11 1993-07-20 Haddad Heskel M Drug delivery ophthalmic insert and method of preparing same

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3995635A (en) * 1971-09-09 1976-12-07 Alza Corporation Ocular insert
US3949750A (en) * 1974-10-07 1976-04-13 Freeman Jerre M Punctum plug and method for treating keratoconjunctivitis sicca (dry eye) and other ophthalmic aliments using same
US4093708A (en) * 1974-12-23 1978-06-06 Alza Corporation Osmotic releasing device having a plurality of release rate patterns
US4014335A (en) * 1975-04-21 1977-03-29 Alza Corporation Ocular drug delivery device
NL188266C (en) * 1975-07-29 1992-05-18 Merck & Co Inc PROCESS FOR THE PREPARATION OF AN ORGANIC IMPLANT.
US4034758A (en) * 1975-09-08 1977-07-12 Alza Corporation Osmotic therapeutic system for administering medicament
US4164559A (en) * 1977-09-21 1979-08-14 Cornell Research Foundation, Inc. Collagen drug delivery device
US5248700A (en) * 1982-05-14 1993-09-28 Akzo Nv Active agent containing solid structures for prolonged release of active agents
US4524776A (en) * 1983-10-27 1985-06-25 Withers Stanley J Split carrier for eyelid sensor and the like
US5322691A (en) * 1986-10-02 1994-06-21 Sohrab Darougar Ocular insert with anchoring protrusions
GB8623661D0 (en) * 1986-10-02 1986-11-05 Darougar S Ocular insert
US5147647A (en) * 1986-10-02 1992-09-15 Sohrab Darougar Ocular insert for the fornix
US5137728A (en) * 1988-03-01 1992-08-11 Bausch & Lomb Incorporated Ophthalmic article
US4975280A (en) * 1989-01-23 1990-12-04 Ethyl Corporation Bioerodable sustained release implants
US5164188A (en) * 1989-11-22 1992-11-17 Visionex, Inc. Biodegradable ocular implants
WO1992000112A1 (en) * 1990-06-25 1992-01-09 Ungerleider Bruce A Apparatus for reducing intraocular pressure

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3828777A (en) * 1971-11-08 1974-08-13 Alza Corp Microporous ocular device
US4730013A (en) * 1981-10-08 1988-03-08 Merck & Co., Inc. Biosoluble ocular insert
US5229128A (en) * 1986-06-11 1993-07-20 Haddad Heskel M Drug delivery ophthalmic insert and method of preparing same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0707464A1 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6264971B1 (en) 1999-11-04 2001-07-24 Btg International Limited Ocular insert
WO2001032140A1 (en) * 1999-11-04 2001-05-10 Btg Int Ltd Ocular insert
US10610407B2 (en) 2004-07-02 2020-04-07 Mati Therapeutics Inc. Treatment medium delivery device and methods for delivery of such treatment mediums to the eye using such delivery device
US9168222B2 (en) 2006-03-31 2015-10-27 Mati Therapeutics Inc. Nasolacrimal drainage system implants for drug therapy
US9610194B2 (en) 2006-03-31 2017-04-04 Mati Therapeutics Inc. Drug delivery methods, structures, and compositions for nasolacrimal system
US11406592B2 (en) 2006-03-31 2022-08-09 Mati Therapeutics Inc. Drug delivery methods, structures, and compositions for nasolacrimal system
US10300014B2 (en) 2006-03-31 2019-05-28 Mati Therapeutics Inc. Nasolacrimal drainage system implants for drug therapy
US10383817B2 (en) 2006-03-31 2019-08-20 Mati Therapeutics Inc. Nasolacrimal drainage system implants for drug therapy
US10874606B2 (en) 2006-03-31 2020-12-29 Mati Therapeutics Inc. Nasolacrimal drainage system implants for drug therapy
US10736774B2 (en) 2009-06-03 2020-08-11 Forsight Vision5, Inc. Anterior segment drug delivery
US10004636B2 (en) 2009-06-03 2018-06-26 Forsight Vision5, Inc. Anterior segment drug delivery
US9937073B2 (en) 2010-06-01 2018-04-10 Forsight Vision5, Inc. Ocular insert apparatus and methods
US9610271B2 (en) 2011-08-29 2017-04-04 Mati Therapeutics Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
US10632012B2 (en) 2011-08-29 2020-04-28 Mati Therapeutics Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
US9974685B2 (en) 2011-08-29 2018-05-22 Mati Therapeutics Drug delivery system and methods of treating open angle glaucoma and ocular hypertension
US10835416B2 (en) 2011-09-14 2020-11-17 Forsight Vision5, Inc. Ocular insert apparatus and methods
US10456293B2 (en) 2012-10-26 2019-10-29 Forsight Vision5, Inc. Ophthalmic system for sustained release of drug to eye
US11224602B2 (en) 2015-04-13 2022-01-18 Forsight Vision5, Inc. Ocular insert composition of a semi-crystalline or crystalline pharmaceutically active agent

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US5395618A (en) 1995-03-07
CA2165071C (en) 2000-08-15
EP0707464A1 (en) 1996-04-24
JPH0767910A (en) 1995-03-14
US5322691A (en) 1994-06-21
CA2165071A1 (en) 1995-01-19
EP0707464A4 (en) 1997-03-26
JP2995137B2 (en) 1999-12-27
WO1995001764A3 (en) 1995-03-02

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