Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-04-01
2001-04-17
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S420000, C424S422000, C424S426000, C424S428000, C424S429000
Reexamination Certificate
active
06217896
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of physiology, physics, drug delivery and medical treatment. More specifically, the present invention relates to non-erodable and erodable conjunctival insert designs and applications of such inserts in the topical delivery of medication and/or lubrication to the inferior and superior conjunctival spaces of the human eye or in treatment of primates and quadrupeds.
2. Description of the Related Art
Ocular inserts are devices containing medication or lubricants that are placed into the inferior or superior conjunctival sacs. Ocular inserts are perhaps more specifically called “conjunctival inserts”. In theory, these devices allow more consistent release of medication or lubricant into the tear fluid over an extended time span in comparison to most other forms of topical ocular drug or lubricant delivery.
The potential advantages of inserts, especially when compared to traditional eye drops or ointments, would include the attainment of more effective therapy with reduced side effects, more efficient delivery of drugs or lubricants over a longer duration, and, perhaps, less dependence on patient compliance for maintenance and success of topical ocular therapy (1). A summary of potential advantages of the conjunctival insert as a device for topical ocular drug delivery appears in Table 1.
TABLE 1
Potential Advantages of Ocular Inserts
Steady, sustained drug release
Reduced overdose/underdose cycle
Lower total dosage required
Reduced short term ocular side effects, miosis, pseudomyopia
Reduced long term ocular side effects, preservative toxicity to
ocular surface
Reduced systemic absorption and side effects
Extended duration of use
In contact with larger tissue surface area
Round-the-clock drug delivery
Reduced need for preservatives, liquid vehicles
Reversibility; take the insert out
Reduced dependance on patient compliance
Several water-soluble and insoluble solid carriers have been used to topically supply medication to the eye. Gelatin wafers called “lamellae” were described as early as 1948 in the British Pharmacopeia, intended for topical application of atropine by placement beneath the eyelid (2). This general idea was revived in Moscow in the mid-1960s when rectangular inserts were cut from thin films of polyvinyl alcohol (PVA) and used to release pilocarpine into the cul-de-sac for treatment of glaucoma (3, 4). The first ocular insert produced in an oval shape was made of an insoluble form of polyvinyl alcohol soaked in pilocarpine for the slow release of medication into the inferior cul-de-sac for the treatment of glaucoma. Initially reported by Maichuk in Moscow in 1974 (5), the polyvinyl alcohol substrate appeared to have been simply punched out of a flat piece of polyvinyl alcohol, its shape similar to that which would have resulted from the use of a paper hole punch. The Maichuk inserts administered pilocarpine by first-order kinetics and the polyvinyl alcohol substrate remained in the eye until removal or expulsion (5, 6).
Additional research and development of ocular inserts were performed during the decade of the 1970s. Inserts of several different physical sizes and shapes were attempted and culminated in a few inserts that were marketed by major pharmaceutical firms. The “Lacrisert”, for treatment of dry eye, is available currently in the form of a hydroxypropyl cellulose rod supplied dry and sterile in a paper/foil package (7). Individual Lacrisert rods are 3.5 mm long by 1.25 mm in diameter and are, evidently, cut from a longer dry rod of material. The unpolished ends of the Lacrisert are often jagged, but may soften and become rounded in the eye as the hydroxypropyl cellulose swells by absorbing fluid and then slowly erodes into the tear film. Thus, the hydrated Lacrisert becomes smaller with time until it erodes away or is expelled from the cul-de-sac.
“Collagen corneal shields” are contact lenses that can be used as or modified into erodable inserts. Made of treated porcine scleral collagen, the shields are in the shape of spherical contact lens shells (diameter 14.5-16.0 mm, base curves 8.8 or 9.0 mm, thickness 0.15-0.19 mm when hydrated) (7, 8). Collagen shields can be prescribed as inserts for dry eye (9) or perhaps the acute, short term treatment of ocular infections after soaking in a suitable antibiotic solution. This device is limited for delivering poorly controlled release of drug over a relatively short time, a few days at most. The erosion of these devices, although theoretically controlled by the manufacturing process, proves clinically to be unpredictable. Such device is fit only as a contact lens, i.e., to the cornea, and not as a conjunctival insert.
The “Ocusert” is considered to be the most advanced conjunctival insert available, as it is the only insert that is intended to supply medication according to zero-order kinetics. Drug release is maintained relatively constant except for an initial burst of drug release in excess of the desired dosage lasting 4-8 hours. Pilocarpine is bound to a flat, thin core of alginic acid sandwiched between two layers of ethylene vinyl acetate. The layers of ethylene vinyl acetate act as permeable barriers that allow controlled release of pilocarpine into the tear film. Two dosages are available from the manufacturer for treatment of glaucoma in slightly different elliptical dimensions: 13.4×5.7×0.3 mm and 13.0×5.5×0.5 mm (7). The elliptical, flat, thin, flexible insert is supplied dry and sterile in a paper-covered plastic storage compartment and is intended to remain in the cul-de-sac for one week until removed.
The most significant problems associated with the use of conjunctival inserts are expulsion and discomfort. At least 27% of 459 patients monitored during the wear of “Ocuserts” reported that these inserts were expelled from the eye (10). A similar percentage of patients reported that the inserts were uncomfortable (10). It is evident that conventional ocular inserts have been designed without adequate attention given to the space into which they were intended to reside. Most inserts have been tested primarily with the inferior human conjunctival sac as the place of residence, though several studies point to the superotemporal conjunctival sac as a better location for certain inserts and especially in some patients. The lack of success of human conjunctival inserts in the marketplace may have occurred because of the failure to maximally utilize the actual volume and shape that could be contained in the cul-de-sacs.
The prior art is deficient in the lack of conjunctival inserts with much improved conformity, larger drug capacity and increased stability within the sacs. The present invention fulfills this long-standing need and desire in the art.
SUMMARY OF THE INVENTION
The present invention is directed to improved conjunctival inserts and uses thereof.
In one embodiment of the present invention, there is provided a conjunctival insert of a crescent shape in the horizontal plane, comprising a central back curvature conforming to the bulbar surface; a horizontal ridge situated approximately ⅔ of the way from the top of said insert; an acute superior edge and a rounded bottom with the most inferior portion at the horizontal middle. Preferably, the back curvature has a radius of from about 12 mm to about 18 mm, and the horizontal ridge is of a crescent shape in the horizontal plane. More preferably, the rounded bottom has a radius of curvature from left to right of from about 20 mm to about 25 mm, a radius of curvature from front to back of from about 0.5 mm to about 1.0 mm. Made in three different designs varying by sizes, such conjunctival insert fits the cul-de-sac of at least 75% of adults and can be placed in either the inferior or superior cul-de-sac of an eye.
In one preferred embodiment, the inserts are made of non-erodable or erodable materials. Examples for non-erodable materials are hydrogel, more preferably silicon hydrogel, and silicon rubber. Examples of
Adler Benjamin Aaron
Dudash Diana
Sharareh Shahnam
UAB Research Foundation
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