Title:  Ocular insert

United States Patent:  6,264,971

Assignee:  BTG International Limited (London, GB)

Filed:  November 4, 1999

A flexible ocular insert device adapted for the controlled sustained release of a drug upon insertion into the upper or lower fornix of the eye. The device comprises an elongate body of a polymeric material including two end portions, wherein the body contains a pharmaceutically active ingredient, and wherein the device has a length of at least 8 mm and a maximum diameter not exceeding 1.9 mm. The device is sufficiently flexible to allow it to bend along the curvature of the eye within the upper or lower fornix upon its being positioned so that the longitudinal axis of the device is generally parallel to the transverse diameter of the eyeball, and the device does not extend onto any visible portion of the eyeball. Each of the end portions of the device is tapered towards the extremities of the device.

SUMMARY OF THE INVENTION

The present invention in a first aspect provides a flexible ocular insert device adapted for the controlled sustained release of a drug upon insertion into the upper or lower fornix of the eye, said device comprising an elongate body of a polymeric material including two end portions said body containing a pharmaceutically active ingredient, said device having a length of at least 8 mm and a maximum diameter 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, and in which each of said end portions is tapered towards the extremities of the device.

It has been found that such a flexible ocular insert device, is well retained in place and tolerated better by the patient over a period of use more prolonged than hitherto possible.

Whereas the flexible ocular insert device of U.S. Pat. No. 5,395,618 permitted use of up to 7 or 14 days or longer in the upper fornix but usually less than 2 days in the lower fornix. Only between 14 to 47% of patients could retain the device in the upper fornix for 28 days or longer. The flexible ocular insert device of the present invention has been found to be retained by 72% of people for 28 days or longer when in the upper fornix and was retained in 36% of people for 28 days or longer when in the lower fornix.

The increased retention of the device fitted in the upper fornix means the device can be used to deliver drugs to the eyes to treat ailments requiring long term continuous treatment, ie one application for the treatment or prevention of infection or allergy or application every 1 to 3 months or longer for chronic diseases. The fact that the device may be fitted and removed by the patients themselves into and out of the upper or lower fornix which, coupled with the high retention period in the fornices now allows the patient to fit a device of the present invention for self application of treatments that would previously have required an experienced person to fit and remove an ocular device to and from the fornices of a patient.

The device is designed to be inserted in the conjunctival folds of the upper or lower fornix at the junction between the palpebral conjunctiva of the upper or lower eyelid and bulbar conjunctiva of the eyeball, being held in position preferably in the extreme outer and inner end portions of the upper or lower fornix and prevented from moving downward or laterally respectively by the pressure and movement of the lid against the eyeball. The tapered end portions, at least in part, lie between the upper or lower tarsus and the eyeball, because they are conical, they serve to prevent the device moving laterally in the fornix whilst also providing a reduced pressure on the eyeball compared to known prior art inserts when similarly positioned in the eyes, thereby providing increased comfort and tolerability for the patient.

The device may include optional radial protrusions acting, in use, to minimise lateral movement of device within the fornix, preferably two protrusions each positioned to lie adjacent the tarsus, in use.

The device may have protrusions extending outwardly a distance such that the overall diameter of the device including the protrusions is approximately 15 to 30% greater than the diameter of the body of said device. They may, for example, be positioned so as to be symmetrical disposed about the centre point of said body.

The protrusions, if present, are preferably toroidal or doughnut shaped around the body to provide a ribbed configuration.

The body of device may include a cylindrical portion between the two end portions or be entirely formed by the two end portions, the end portions having a common base. The tapered end portions may each be in the form of a right circular cone or an oblique circular cone. Preferably, the apex of each end portion is rounded.

The length of the device is conveniently from 8 to 25 mm for use in the lower fornix to suit the eyes of different sizes such as infants, children and adults, or from 8 to 35 mm for use in the upper fornix to suit the eyes of different sizes such as infants, children and adults.

The diameter of individual devices including protrusions is preferably from 0.5 to 1.9 mm to suit the eyes of different sizes such as infants, children and adults.

The mechanism of drug release may be, for example, by diffusion through an outer wall of the device, osmosis, bioerosion, or diffusion including possible drug dissolution.

The polymeric material of the device may be, for example, a silicone elastomer, made of hydrogel components or be a methacrylate or hydroxymethacrylate based material.

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 that provides for anchoring the device across the fornix. Two or more protrusion elements, when present, 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 or the lid by virtue of the fornix anatomy. In contrast, a device placed anywhere on the bulbar conjunctiva would be subject to eye and or lid 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 in 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 or lid movement and does not move when the eye or lid moves. The conical end portions improve retention in the required position whilst at the same time reducing adverse effects so leading to improved retention characteristics. The device of the present invention also retains 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 10 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.

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 sulfonomides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals including idoxuridine, trifluorothymidine, acyclovir, gancyclovir and interferon; non-antibiotic, anti-infection, anti-bacterial or anti-microbial drugs such as iodine based preparation triclosan, chlorhexidine,et al; anti-allergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, cetirizine and prophenpyridadine; anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluorocinolone, medrysone, prednisolone acetate, fluoromethalone, betamethasone, and triamcinolone and non-steroidal agents such as indomethacin, diclofenac, flurbiprofen, piroxicam, ibuprofen and acetylsalicylic 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 demecarium 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, levobunclol HCl and betaxolol Hcl; 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; angiogenesis inhibitors such as steroids, angiostatin, antiproliferative agents such as flurouracil and mitomycin.

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(vinylpyrrolidone), alone, or with suitable dispensing agents such as lecithin, polyclylic acid derivatives 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. Pat. No. 4,186,184 and in "Therapeutic Systems" by Klaus Heilmann 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 defines a reservoir for the drug which is in liquid or gel form. At least the lateral 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 device comprises a transverse impermeable elastic membrane dividing the 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 and 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 bierosion mechanism, the configuration of the body of the insert device is 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 body 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 monastearate and oils, gum tragacanth, sodium alginate, polylvinyl 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 hydrolysed 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 --0--(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 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).

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 copolymers 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 (alkyl-2-cyanoacrylates) such as poly (hexyl-2-cyancacrylate) as described by Douglas et al. (1987), Nanoparticles in Drug Delivery, CRC Crit. Rev. Therap. Drug Carr. Syst., 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. Pat. 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.

Accordingly to a second, independent, aspect of the present invention a flexible ocular insert device adapted for the controlled sustained release of two or more drugs upon insertion into the upper or lower fornix of the eye, said device comprising an elongate body of a polymeric material including two end portions said body containing a pharmaceutically active ingredient, said device having a length of at least 8 mm and a maximum diameter 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, and in which at least two distinct portions of the device include respective distinct ones of said drugs.

This permits the use of synergistic, additive, supportive or complementary drugs for improved patient treatment in which the drugs are not mixed before release but which mix in the eye after independent release from the device. This avoids the need for regulatory studies on the mixture for antagonism and so on.

The different drug's release rates can be adjusted to be optimal for each drug by independently tailoring the characteristics of the different drug bearing elements of the device.

It should be noted that this aspect of the invention does not require the device to have tapered end portions or anchoring protrusions, these being entirely optional features as regards the invention is its second aspect.

On the other hand, all the embodiments of tapered end portion devices described in relation to the tapered end portion devices according to the first aspect of the present invention may also incorporate the invention in this second aspect by forming distinct portions of each of these embodiments with distinct respective drugs for controlled release of those distinct drugs.

Such multiple drug devices can be made by the same methods described in relation to the single drug release embodiments with suitable modifications. For example, they may be formed by injection molding in which each distinct material is forced into the device mold via distinct passageways so the distinct drug containing portions of the device are formed simultaneously as portions of a unitary device.

Alternatively, the distinct drug portions may be formed by separate molding processes as employed in a single drug delivery system and the portions joined together to form the final device, eg by use of a suitable adhesive.

Claim 1 of 32 Claims

What is claimed is:

1. A flexible ocular insert device adapted for the controlled sustained release of a drug upon insertion into the upper or lower fornix of the eye, said device comprising an elongate body of a polymeric material including two end portions said body containing a pharmaceutically active ingredient, said device having a length of at least 8 mm and a maximum diameter 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, the device does not extend onto any visible portion of the eyeball, and in which each of said end portions is tapered towards the extremities of the device.

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