CA1036883A - Ocular drug dispensing device and process for making the same - Google Patents

Abstract

A B S T R A C T
An ocular drug dispensing device for administering a drug at a controlled and continuous dosage unit rate to the eye to produce a local or systemic physiological or pharmacological effect is comprised of a shaped body insoluble in tear fluid and comprised of a first wall, a third wall distant from the first wall, a second wall interposed between the first and third wall and extending around their peripheries for sealingly engaging the first and third wall, a reservoir defined by the inner surfaces of the walls and containing the drug or a mixture of the drug in a carrier and wherein at least one of the first and third walls is formed of an imperforate drug release rate controlling material permeable to the passage of drug or a microporus material containing in the micropores a drug release rate con-trolling medium permeable to the passage of drug for administering a thera-peutically effective amount of drug over a prolonged period of time.

Description

~036B~3 This invention relates to an ocular drug dispensing device for administering a drug to the eye at a controlled and continuous dosage rate, and to a process for making such a device.
One of the first ocular devices for dispensing drugs directly to the eye consisted of a lamella of a drug dissolved or dispersed in a water sol-uble gel of glycerinated gelatin that was applied to the inner surface of the eyelid. The glycerinated gelatin dissolved rapidly in tear fluid with an accompanying quick release of drug to produce the same kind of effect as liquit tosage forms such as eye drops or ointments. Such lamellae do not provide sustained dispensing and they are not generally used in ophthalmic therapy. See Remington's Pharmaceutical Sciences, Ed. XIII, pages 547 to ~ 548, 196S, published by Mack Publishing Co., Easton, Pa., and An Introduction ; to Pharmaceutical Fo D lation, by Fishburn page 116, 1965, published by Pergamon Press Ltd., New York, N.Y.
Recent advances for administering a drug to the eye are disclosed in United States Patent Nos. 3,416,530 and 3,618,604 owned by Applicant.
These patents describe ocular inserts that act as a depot or drug reservoir for slowly releasing drug to the eye for prolonged periods of time. The in-serts are fabricated of flexible polymeric materials that are biologically ; 20 inert~ non-allergenic, and insoluble in tear fluid. To initiate the ther-apeutic program, these ocular inserts are placed in the cul-de-sac between the sclera of the eyeball and the eyelid for administering drug to the eye.
Since the ocular inserts are formed of polymeric materials that are insoluble - in tear fluid they retain their shape and integrity during the course of the needed therapy to serve as a drug reservoir for continucusly administering drug to the eye and the surrounding tissues at a rate that is not affected by dissolution or erosion of the polymeric material. The ocular insert, on termination of the desired therapeutic program, is removed from the cul-de-sac. Thus, the inserts of the above mentioned patents provide a complete ophthalmic dosage regime for a prolonged period of time, generally on the order of 24 hours or longer.
The device of United States Patent No. 3,416,530 is manufactured `' -1- ~

1(~36BB3 with a plurality of capillary openings that communicate between the exterior of the device and an interior chamber generally defined from a polymeric membrane. While these capillary openings and this construction are effective for releasing drug to the eye, they add considerable complexity to the man-ufacture of the device because it is difficult to control the size of these openings in large scale manufacturing using various polymers as required for various drugs.
The device of United States Patent No. 3,618,604 does not involve such capillary openings, but instead provides for the release of drug by diffusion through a polymeric membrane at a drug release rate that can be controlled with precision and reproducibility. The device of that patent can be a polymeric matrix with the drug dispersed therethrough, or it can be a sealed container having the drug in an interior chamber thereof, such as, of a circular or ellipsoidal cross section.
While these drug dispensing devices of the above-mentioned patents are remarkably effective for administering a drug to the eye, certain problems have been encountered in manufacturing the devices of various polymeric mat-erials. Por example, one manufacturing problem encountered is the difficult task of sealing the msrgins of the polymeric membrane to form the desired container. Another problem encountered in manufacturing an ocular device containing a drug formulation is the need to stretch the polymeric membranes for sealing at their margins. Such stretching is frequently hard to do with-out entrapping excess air or changing the surface area of the membrane.
The ocular drug dispensing devices of this invention comprise a sealed container shaped for insertion in a cul-de-sac of the eye whose wall defines a closed reservoir containing a drug which diffuses through the wall characterized in that the container is formed from a first wall and a third wall spaced from each other, each being insoluble in tear fluid and at least one being permeable to the drug by diffusion at a predetermined rate, and a second ring-shaped wall interposed between and sealed to the first and third walls at their outer perimeters so as to provide the spacing therebetween, the closed drug containing reservoir being defined by the inner surfaces of 103~i883 the first, second and third walls.
The process of the invention for making the above described ocular drug dispensing devices comprises: forming a first wall from a material in-soluble in tear fluid and optionally permeable to drug at a predetermined rate and in a shape and size adapted for insertion in a cul-de-sac of the eye;
forming a second wall from a material insoluble in tear fluid in a ring shape having an outer perimeter of generally the same shape as the perimeter of the first wall; placing the second wall on the first wall with the outer perimeter of the second wall in general registry with the perimeter of the first wall;
charging drug onto the surface of the first wall in the area thereof bounded by the inner perimeter of the second wall; forming a third wall from a mater-ial insoluble in eye fluid and optionally permeable to drug at a predetermined rate, with the proviso that at least one of the first and third walls is per-meable to drug at a predetermined rate, in the same general shape as the first wall; placing the third wall over the drug with its perimeter in general registry with the outer perimeter of the second wall and its periphery con-tacting said second wall; and sealing the first and third walls to the second walls.
In the drawings, which are not drawn to scale but rather are set forth to illustrate various embodiments of the invention:
Figure 1 is a top plan view of an ocular drug delivery device of the invention;
Figure 2 is an enlarged cross-sectional view of the device of Figure 1 taken along line 2-2 of Figure l;
Figure 3 is a miniaturized exploded view of the walls of the device of Figure l;
: Figure 4 is a partly diagrammatic, front elevational view of a human eye illustrating an ocular drug delivery device of this invention in an operative position after its insertion into the eye; and Figure 5 is a view partly in vertical section and partly diagrammat-ic of an eyeball and the upper and lower eyelids associated therewith showing the novel ocular insert of this invention in drug administration operative 1036t~3 position.
One embodiment of the ocular drug dispensing device of this invent-ion is indicated in Figure 1 by numeral 10. Device 10 is comprised of a wall 11 for~ed of a drug release rate controlling material permeable to the passage t3 of a dR~g ~4, as by diffusion. Wall 11 carries on its inner surface an inner positioned wall 12, schematically illustrated by dashed lines, which wall 12 extends around the perimeter of wall 11 to engage it in sealing relation with another wall, not shown in Figure 1, and spaced from wall 11 to form device 10.
Referring to Figure 2, ocular drug delivery device 10 is seen in cross-section along line 2-2 of Figure 1. As seen in Figure 2, device lO is comprised of a first wall 11 and a third wall 14 distant from the first wall 11. Wall 11 and wall 14 bear on their inner surfaces a second wall 12 that extends around the outer perimeter of wall 11 and wall 14 to form a closed reservoir 15. Reservoir 15 contains a drug 13, or a mixture of drugs. Wall 11 and wall 14 can be the same or they can be different and at least one of the walls, 11 or 14, or both of the walls, is comprised of a flexible, substant-ially homogeneous substantially imperforate drug release rate controlling material permeable to the passage of drug 13 as by diffusion. Alternatively at least one of the walls, 11 or 14, is comprised of a flexible microporous material, the micropores of which contain a drug release rate controlling medium permeable to the passage of drug 13, as by diffusion. When one of walls 11 and 14 is permeable to the passage of drug 13, the distant wall can optionally be formed of a material essentially impermeable to the passage of drug or of a material permeable to drug of either the homogeneous or micro-porous types described above. Wall 12 of device 10 is formed of a flexible, non-allergenic, biologically inert, material insoluble in tear fluid which is suitable for joining wall 11 and wall 14 together to form an essentially clos-ed reservoir 15 as defined by the inner surfaces of the walls 11, 12 and 14.
Drug 13, is preferably in a solid form, either neat or mixed with a carrier.
3Q The parts of device 10 act in concert as an ocular drug dispensing device to effectively dispense a drug to the eye and to its surrounding 10~;88~
tissues at a controlled and continuous rate for a prolonged period of time.
When wall 11 or wall 14 is comprised of a material that is substantially homogeneous and imperforate, molecules of drug dissolve in and migrate through the material itself by diffusion. When wall 11 or wall 14 is made from a microporous material, molecules of drug migrate by diffusion through a liquid phase present in the pores of the microporous material. Nall 11 or wall 14 may also be made from a material which is both microporous and permeable to the drug itself. In such a device, drug can be released to the eye by diffusion through the polymer material itself and by diffusion through a dif-fusive medium within the pores of the material.
Wall 12, positioned between wall 11 and wall 14, functions as a bonding or joining wall used essentially for joining wall 11 and wall 14 in a spaced relationship. Wall 12 is formed of a material that readily lends it-self for sealingly engaging walls 11 and 14 to form a flexible, sealed device.
Wall 12 may be optionally comprised of a material permeable or impermeable to drug since its exposed surface area in contact with the eye and its surround-ing tissues is small compared with the total exposed surface area of walls 11 and 14.
Referring to Figure 4 device 10 is shown positioned in immediate contact with an eye 16 for administering a drug thereto. Eye 16 is comprised of an upper eyelid 17 with eyelashes 19 at the edge of eyelid 17 and a lower eyelid 18 with eyelashes 20 at the edge of eyelid 18. Eye 16 anatomically is comprised of an eyeball 22 covered for the greater part of its posterior area by a sclera 24 and at its central area by a cornea 21. Eyelids 17 and 18 are lined with an epithelial membrane or palpebral conjunctiva, not shown, and sclera 24 is lined with a bulbar conjunctiva which covers the exposed surface of eyeball 22. Cosnea 21 is covered with a transparent epithelial membrane, not shown. The portion of the palpebral conjunctiva which lines upper eyelid 17 and the underlying portion of the bulbar conjunctiva defines an upper cul-de-sac, not seen in Figure 4, while that portion of the palpebral conjunctiva which lines lower eyelid 18 and the underlying portion of the bulbar conjunctiva define a lower cul-de-sac, not seen in Figure 4. Device -1~368~3 10 may be shaped and sized for insertion in the cul-de-sac of the conjunctiva between sclera 24 of eyeball 22 and upper eyelid 17, or as seen in broken continuous line, may be shaped and sized for positioning in the cul-de-sac of the conjunctiva between the sclera 24 of eyeball 22 and lower eyelid 18, generally to be held in position by the natural pressure of the respective eyelid.
In Figure 5, eye 16 is shown in horizontal section with device 10 in position to dispense drug. Eye 16 is comprised of upper eyelid 17 and lower eyelid 18, with their respective eyelashes 19 and 20, eyeball 22, cornea 21 and sclera 24. An upper cul-de-sac 26 and a lower cul-de-sac 23 are defined by a conjunctiva 25. Device 10 is positioned in lower cul-de-sac 23 to continuously dispense a predetermined amount of drug or a combination of drugs from the device to the eye and its surrounding tissues over a pro-longed period of time. In operation, after drug leaves the device, it is transported to the eye and its surrounding tissues, by physiological proces-ses such as the flow of tear liquid and blinking action of the eyelids.
The device of this invention can be any convenient geometric shape for confortable retention in the cul-de-sac of the eye such as ellipsoid, bean-shaped, banana-shaped, circular-shaped, rectangular-shaped, trapezoidal or doughnut-shaped. In cross-section, it can be doubly convex, concavo-convex or rectangular, as the device in operation will tend to conform to the Configuration of the eye. The general dimensions of the device may vary de-pending on the amount of drug in the device's reservoir, the rate at which the drug is to be administered to the eye and the size of the eye. Satis-factory devices for insertion in the cul-de-sac of the eye generally have a length of 4 to 20 millimeters, a width of 1 to 15 millimeters, and a thickness of 0.1 to 4 millimeters, and contain from 1 microgram to 100 micrograms of drug or more.
Materials suitable for fabricating the wall~s) of the imperforate, substantially homogeneous type described above include naturally occurring or synthetic materials that are biologically compatible with body fluids and eye tissues, and essentially insoluble in body fluids with which the material 103~W , will come in contact. The use of rapidly dissolving materials or materials highly soluble in eye fluids is to be avoided since dissolution of the wall would affect the constancy of the drug release, as well as the capability of the system to remain in place for a prolonged period of time. Exemplary naturally occurring or synthetic materials suitable for fabricating such walls are poly~methylmethacrylate), poly(butylmethacrylate), plasticized poly ~vinylchloride~, plasticized nylon, plasticized soft nylon, plasticized poly(ethylene terephthalate), natural rubber, polytisoprene), poly(isobutylene), poly(butadiene, poly(ethylene), poly(tetrafluoroethylene), poly(vinylidene chloride), poly(acrylonitrile), cross-linked poly(vinylpyrrolidone), poly ~trifluorochloroethylene), chlorinated poly(ethylene), poly(4,4'-isopropyl-idene diphenylene carbonate), ethylene-vinylacetate copolymer, plasticized ethylene-vinylacetate copolymer, vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumerate copolymer, silicone rubbers, especially the medical grade poly(dimethylsiloxanes), ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer and vinyldiene chloride-acrylonitrile co-polymer.

As stated above such homogeneous imperforate materials dispense drug by a process of diffusion. In that process, the drug dissolves and equilibrates in the material at the inner surface of the wall, and then dif-fuses in the direction of lower chemical potential, i.e., toward the exterior surface of the wall. At the exterior surface of the wall equilibrium is again established. When the conditions on both sides of the wall are main-tained constant~ a steady state flux of the drug will be established in accordance with Fick's Law of Diffusion. The rate of passage of the drug through the material by diffusion is generally dependent on the solubility of the drug therein, as well as on the thickness of the wall. This means that selection of appropriate materials for fabricating the wall will be de-p0ndent on the particular drug to be used. By varying the composition and thickness of the wall, varying dosage rates per area of the ocular device can be obtained.

Materials of the microporous type suitable for fabricating the wall(s) have pores which range in size from several angstroms, usually at least about 10 A, to several hundred microns but usually not more than about 100 microns. The porosity of these materials may range between about 5% and about 95%. Exemplary microporous materials are regenerated, insoluble, nonerodible cellulose, acylated cellulose, esterified celluloses, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate diethyl-amino-acetate, poly(urethanes), poly(carbonates), microporous polymers formed by coprecipitation of a polycation and a poly-anion as described in United States Patents 3,276,589; 3,541,005; 3,541,006 and 3,546,142, modified insoluble collagen, cross-linked poly tvinyl alcohol) with a pore size of 7 to 50 A, epoxy resins and poly(olefins) or poly(vinyl-chlorides) with a pore size of about 50 A or less to 150 microns or larger as conveniently made by leaching out incorporated salts, soap micelles, starch or like materials to give a microporous membrane. Also, the materials that can be uset include those materials having homogeneous properties and micro-porous properties, such as cross-linked gelatinous membranes. As indicated above such microporous materials dispense drug by a process in which the drug diffuses through a diffusive medium in the pores of the material. In this process, the drug molecules dissolve in the medium at the interior surface of the wall and flow through the medium in a direction of lower chemical potential, that is, to the exterior surface of the wall. A drug will have a definite and characteristic rate of diffusion through the diffusive medium which is general-ly dependent on the solubility of the drug in the diffusive medium, the thick-ness and porosity of the release rate controlling material and the tortuosity factor.
The diffusive media suitable for use with the microporous materials are those materials which are non-toxic in the eye and surrounding tissues and in which the drug has a limited solubility so that the drug is released by diffusion rather than by simple dissolution which is difficult to control.
By limited solubility is meant that drug is soluble in given selected amounts in the diffusive medium and includes solubilities such as soluble, sparingly 1036~
soluble, slightly soluble, vary slightly soluble, and almost practically insoluble. Generally, the term 'llimited solubility" comprises a range of solubility of d~ug in medium of from 10 parts per million to 10,000 parts per million on a weight basis.
The medium can be a liquid, a gel, a colloidal solution, a sol, and the solution can be polar, semi-polar, or non-polar. Representative mediums are saline, glycerin, ethylene glycol, propylene glycol, water, emulsifying and suspending agents such as methyl cellulose mixed with water, mixtures of propylene glycol monostearate and oils, gum tragacanth, sodium alginate, poly(vinyl pyrollidone), polytoxyethylene stearate), fatty acids such as linoleic, and silicone oil. Other representative mediums are set forth in Remington's Pharmaceutical Sciences, pages 24~ to 269 and 1338 to 1380, 1970, published by Mack Publishing Company, Easton, Pa.
The diffusive medium can be added to the microporous material by methots well known to the art, for example, by immersion of the material in a bath containing the diffusive medium to let the medium partially fill or fully saturate the micropores of the material. Another method for charging the micropores with a diffusive medium is to add the diffusive medium or a mixture of diffusive media with the drug formulation so that the medium can flow from within the reservoir into the pores and remain therein to permit diffusive flow of drug. In a preferred aspect, the diffusive medium is an isotonic solution such as lachrymal fluid which can be incorporated into the pores of the microporous material by way of the previously described methods or advantageously incorporated by contact with the eye at the time the ocular device is inserted in the eye, in which case these fluids are available for subsequent transfer into the micropores of the material for functioning as a diffusive medium for drug.
Materials suitable for forming the second wall that is interposed between the first and third walls and sealingly joins the same at their per-imeters are naturally occurring and synthetic materials that can serve as a cold setting adhesive or as a hot setting adhesive with tackiness while simul-taneously retaining their polymeric integrity to serve as the middle wall ~03~W
and assist the two spaced walls in defining the reservoir. The phase ~cold setting adhesive" as used herein indicates polymeric materials that are tacky and will bond other polymeric materials at set temperatures from 5 & to 50C, and the phrase "hot setting adhesive" is used to indicate a polymeric material that is tacky and will bond other polymers at set temperatures from 50C to 250C. The term "tacky" generally indicates stickiness of a polymeric material to intimately bond two walls together. The operable temperatures for such bonting polymers can easily be ascertained by standard techniques as set forth in Modern Plastic EncycloPedia, Vol. 46, No. lOA, 1969, and in ASTM
Standards, Structural Sandwich Constructions, Part 16, T. Peel Test: ASTMD
1876-61 T. Peel Resistance, 1965, published by the American Society for Test-ing and Materials, and like references. Exemplary materials are polytvinyl-acetate), cross-linked poly(vinyl-alcohol), cross-linked poly(vinylbutyrate), ethylene-ethyl acrylate copolymer, poly(ethyl hexylacrylate), poly(vinyl-chloride), polytvinyl acetals), plasticized ethylenevinylacetate copolymer, poly(vinylalcohol), polytvinylacetate), ethylene-vinylchloride copolymer;
polytvinylesters~, poly(vinylbutyrate), poly(vinylformal) and polyamides.
The use of an intermediate second wall in the devices provides several advantages. It enables easy manufacture of a sealed container from materials of different drug diffusion properties. Also colors, that is dyes, may be incorporated into the second wall to serve to identify different drugs, different sized devices and dates of manufacture. Additionally, the dye is not mixed with the drug so potential dye-drug complexes are avoided. Another important advantage of the middle wall is its ability to function as an adhes-ive to seal together at low temperatures like walls or unlike walls into a composite article of manufacture. Thus, walls formed of materials like poly-(vinylchloride) that would require a high sealing temperature, e.g., 200C or higher, can be hermetically sealed by using a middle wall of for example, ethylene/vinyl acetate copolymer that serves as a hot melt adhesive to join the first and third walls at a much lower temperature. Additionally, the middle wall by functioning as a hot melt adhesive can be used to seal general-ly unsealable walls, for example walls formed of unplasticized cellulose 1036~3 acetate. Sealing at low temperatures also protects the drug from exposure to high temperatures that could alter or adversely affect the drug.
As used herein the term "drug" broadly means compositions administ-rable to the eye and its surrounding tissues to produce a local or a systemic physiologic or pharmacologic beneficial effect. Examples of drugs include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin; anti-bacterials such as sulfonamides, sulfacetamide, sulfame-thizole and sulfisoxazole; antivirals, including idoxuridine; and other anti-bacterial agents such as nitrofurazone and sodium propionate; anti-allergenics such as antazoline, methapyriline, chlorpheniramine, pyrilamine and prophen-pyrîtamine; anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, pred-nisolone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone and triaminolone; decongestants such as phenyl-ephrine, naphazoline, and tetrahydrazoline; miotics and anticholinesterases ; such as pilocarpine, eserine salicylate, carbachol, di-isopropyl fluoro-phosphate, phospholine iodide, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; and sympathomimetics such as epinephrine.
Generally an ocular drug delivery device will contain from 1 microgram to 100 milligrams of drug or more for releasing the drug to the eye at art known dosage rates. For example, an ocular drug delivery device can administer 5 to 200 micrograms per hour of pilocarpine and its derivatives for 24 hours to an adult human, or for simultaneous administration of 5 to 120 micrograms of pilocarpine hydrochloride and 10 micrograms to 0.5 milligrams of hydrocortisone acetate for a daily dose, and the like as described in standard in Physicians' Desk ~eference, Drug Classification Index, Ophthalmologicals, page 217 and entires cited therein, Twenty-Fourth Edition, 1969, Medical Economics, Inc.
Drugs can be in various forms, such as uncharged molecules, compon-ents ofmoleculearcomplexes, or non-irritating, pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, ~03~883 acetate, maleate, tartrate and salicylate. For acidic drugs, salts of metals, amines, or organic cations, for example, quaternary ammonium can be employet.
Furthermore, simple derivatives of the drugs such as ethers, esters, amides, and the like, which have desirable retention, release or solubility character-istics, and which are easily hydrolized by body p~, enzymes, or other meta-bolic processes can be employed.
The drug is desirably present in the interior reservoir defined by the walls of the device in a manner, mode and quantity in which it will be in intimate contact, at a constant thermodynamic activity, with the drug-per-meable wall(s) of the device throughout the administration period. For this purpose and for fabricating convenience it will preferably be present together with a drug permeable solid or semi-solid (e.g., a gel or colloid) carrier which provides a formulation which may be cast or otherwise formed into a body which may be readily handled and assembled in combination with the walls.
In this regard it is possible to use liquid drugs or liquid drug formulations in the devices of this invention. ~lowever, the use of such liquids presents greater handling and assembling problems than the use of solid materials. To readily maintain such thermodynamic activity the drug should have limited solubility in the carrier and be present in sufficient excess to initially saturate the carrier and maintain such saturation during the drug administrat-ion period. By limited solubility is meant that drug is soluble in given amounts in the carrier, that is, it comprises varying concentrations of drug dissolved in the carrier. In most instances the drug will be soluble in the carrier in amounts ranging between 10 and 10,000 p.p.m. As indicated above there is also an excess amount of undissolved drug present in the carrier.
The initial fractional amount of drug dissolved in the carrier will usually be in the range of 0.1% to 35% by weight of the total amount of drug. In any event there should be sufficient undissolved drug incorporated to serve as a reserve source of drug for replacing released drug by dissolving in the carrier to keep the concentration of drug in the carrier at its saturation concentration during the history of the ocular device, or until the ocular device is no longer used. Examples of solid and se~i-solid carriers are gelatin, starches, carbohydrates, solid extracts, cured polymers, silicone carbonate copolymers, plasticized polymers, hydrophilic polymers such as hydrophilic hydrogels of esters of acrylic acids, modified collagen, surface treated silicone rubber, alginic acid and derivatives thereof, pectin and plasticized poly(vinylchloride). The carrier can also contain adjuvants such as preserving, stabilizing, or wetting agents.
The materials forming the drug-permeable wall and the carrier are preferably chemically and structurally different within a single device so that the rate of drug release through the wall primarily determines the rate at which the drug is dispersed. In other worts the rate of permeability through the wall is materially less than the rate of permeability through the carrier.
The carrier-drug mixture may be prepared by standard mixing tech-niques such as ballmilling, calendering, shaking and rollmilling.
The device may be assembled by standard procedures such as by molding or casting the first wall, pressing the second annular wall thereto, extruding drug into the reservoir, then sealing the third wall in place as shown in the drawing. The walls can be sealed together by various methods such as high frequency electronic sealing that provides clean edges and firmly sealet ocular devices. By using, for example, high frequencing sealing, the wall orming materials flow melt at the point of contact to suitably join the walls into a composite article of manufacture. The ability to design and shape the walls into an ocular device of highly reproducible shapes, readily results in fabrication of ocular drug delivery devices with reproducible dispensing prop-erties and thus overcomes a significant disadvantage of previously described devices. Other standard manufacturing procedures are described in Modern Plastics Encyclopedia, Vol. 46, pages 62 to 70, 1969, and may be readily adapted by those skilled in the art to fabricate the ocular device of the invention.
The following examples are merely illustrative of the present invention and they should not be considered as limiting its scope in any way.
EXAMPLE
An ocular drug dispensing device of elliptical shape and comprised of two outer drug release rate controlling walls each fused to an inner middle wall having a center area defining a space and which middle wall extends around and interbonds the internal perimeter of the two outer walls to form an ocular drug dispensing device having a reservoir for containing a drug defined by the internal surfaces of all the walls is manufactured as follows:
first, a uniform wall material is formed by dissolving commercially available ethylene/vinyl acetate copolymer in methylene chloride in a concentration ratio or 20% copolymer to 80% solvent and film casting the solution onto a glass substrate. The solvent is allowed to evaporate at room temperature and the film warm-air dried to yield a film about 1.7+0.2 mils thick. Two walls, about 16 mm x 6.75 mm, are pressed from the film for use as the drug release walls of the ocular device. Next, a middle wall is prepared by mixing ethyl-ene/vinyl acetate copolymer, methylene chloride and Food Drug and Cosmetic blue lake dye in a per cent ratio of 20 to 80 to 0.1 and the ingredientS
thoroughly mixed in a commercial, laboratory v-blender. The mixture is cast onto a glass surface, and the solvent evaporated at room temperature. Then, the film is warm air dried to yield a film 4.2~0.3 mils thick. Next, this film is press cut into an ellipse having the same dimensions of the just press cut walls. The middle wall is press cut w~th the center area punched out to yield a continuous ellipse defining an opening. Then, onto one of the drug release walls is placed the middle wall and these two walls placed into a con-ventional standard vacuum laminator. Next, a vacuum is pulled to 74 cm. of mercury and held for three minutes. At the end of three minutes, a high flux radiant heater is positioned over the walls and heated for about 15 seconds or until the temperature reaches about 70C. At the end of the heating, a pres-sure head is applied to the two walls and a pressure of 6.8 Kg, applied for 45 seconds to firmly seal the two walls, and the vacuum released.
Next, to 500 grams of sterile, distilled water is added 300 grams of pilocarpine base and 25 grams of alginic acid and the ingredients well mixed in a standard vYblender, and following the mixing cast on a clean glass plate.
The water is evaporated at room temperature to yield an alginic acid-pilo-carpine drug core, of approximately 92.3% pilocarpine base and 7.7% alginic acid. A 7.0,1.0 mg aliquot of the drug core is then deposited into the two wall laminate, and the third wall placed in contact with the middle wall.
The three walls are then vacuum, heat laminated as just described to produce a composite article of manufacture. The resulting device, when placed into an adult human eye, will administer 50 micrograms of pilocarpine per hour for 24 hours.

An ocular drug delivery device for the prolonged, continuous and controlled rate of drug administration is manufactured from drug release rate controlling material insoluble in eye fluid according to the procedure as described in Example 1 with the drug reservoir in this embodiment comprised of pilocarpine and alginic acid wherein the ratio of pilocarpine to alginic acid is from 12 to 1 and from 3 to 1 for the controlled release of the drug to the eye.

Following the procedure set forth in Example 1, an ocular drug dispensing device shaped like a circle 6 mm x 2.5 mm is prepared according to the described procedure, except one of the drug delivery walls is formed from commercially available nylon-66, the dye is approved red, and the drug in the reservoir is hydrocortisone acetate. The area of the device is 1 cm2 and the walls are 2 mils thick with the drug release rate for the ethylene/vinyl acetate copolymer wall about 40 micrograms per hour and the drug release rate for the nylon wall about 2 micrograms per hour.

Following the procedure set forth in Example 1, an ocular drug dispensing device is prepared wherein one drug release wall is cellulose acetate, the middle wall is dye free, and the other drug release wall is silicone rubber. The drug release rate for hydrocortisone alcohol through a 1 cm2 area wall that is 2 mils thick is 3 micrograms per hour for the cel-lulose acetate wall, and 200 micrograms per hour for the silicone rubber wall.

An ocular drug dispensing device of banana shape, 21 mm x 5 mm x 10~
0.25 mm, for administering a drug to the eye over a prolonged period of time at a uniform and continuous rate is prepared as follows: a drug/carrier mix is first prepared by mixing liquid polydimethylsiloxane with 2000 micrograms of hydrocortisone alcohol and stannous octoate catalyst, 0.5% by weight, and charging the mixture into a preshaped banana mold having dimensions that cor-respond to the reservoir volume of an ocular drug dispensing device. The drug/
carrier mixture is allowed to cure at room temperature and then removed from the mold. Next, the thus molded mixture is placet into the reservoir of an ocular device that is comprised of a drug release rate controlling cellulose acetate wall having bonded onto its internal surface an ethylene/vinyl acetate copolymer banana-shaped ring. Then, the cellulose acetate wall is heat sealed under vacuum and pressed onto the free surface of the ring to yield an ocular drug dispensing device. The drug dispensing walls are characterized by a porosity of 60%, a pore size of 0.45 micron and a thickness of 4 mils. When the device is inserted in the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lower lid, it is effective for administering the ster-oid at a controlled rate at a therapeutically effective dose to the eye for 24 hours.
eXAMPLe ~
An ocular dispensing device is manufactured in a rectangular shape by laminating according to the procedure of Example 1, to the outer marginal area of an inner ethylene/vinyl acetate copolymer wall having a space in its central area, two outer walls, one of cellulose butyrate and the other of poly~propylene) to define between the two outer walls and interior reservoir for containing a pharmaceutical composition comprised of a drug and a carrier.

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An ocular drug dispensing device for dispensing drug to an eye at a predetermined rate for a prolonged period of time comprising a sealed contain-er shaped for insertion in a cul-de-sac of the eye whose wall defines a closet reservoir containing a drug which diffuses through the wall characterized in that the container is formed from a first wall and a third wall spaced from each other, each being insoluble in tear fluid and at least one being per-meable to the drug by diffusion at a predetermined rate, and a second ring-shaped wall interposed between and sealed to the first and third walls at their outer perimeters so as to provide the spacing therebetween, the closed drug containing reservoir being defined by the inner surfaces of the first, second and third walls.

2. An ocular drug dispensing device in accordance with claim 1 wherein said one wall that is permeable to the drug by diffusion at a predetermined rate is formed of a substantially homogeneous and substantially imperforate polymeric material.

3. An ocular drug dispensing device in accordance with claim 1 wherein the first and third walls are both permeable to the drug by diffusion at a predetermined rate.

4. An ocular drug dispensing device in accordance with claim 1 wherein said one wall that is permeable to the drug at a predetermined rate is formed of a microporous polymeric material the pores of which contain a medium in which the drug has limited solubility and which is permeable to the drug at the predetermined rate.

5. An ocular drug dispensing device in accordance with claim 1 wherein the second wall is formed of a cold setting adhesive, polymeric material.

6. An ocular drug dispensing device in accordance with claim 1 wherein the second wall is formed of a hot setting adhesive, polymeric material.

7. An ocular drug dispensing device in accordance with claim 1 wherein the second wall has a dye incorporated in it which makes its color distinct from the colors of the first and third walls.

8. An ocular drug dispensing device in accordance with claim 1 wherein the first and third walls are formed of ethylene/vinyl acetate copolymer.

9. A process for making an ocular drug dispensing device for dispensing drug to an eye at a predetermined rate for a prolonged period of time char-acterized by: (a) forming a first wall from a material insoluble in tear fluid and optionally permeable to drug at a predetermined rate and in a shape and size adapted for insertion in a cul-de-sac of the eye; (b) forming a second wall from a material insoluble in tear fluid in a ring shape having an outer perimeter of generally the same shape as the perimeter of the first wall; (c) placing the second wall on the first wall with the outer perimeter of the second wall in general registry with the perimeter of the first wall;
(d) charging drug onto the surface of the first wall in the area thereof bounded by the inner perimeter of the second wall; (e) forming a third wall from a material insoluble in eye fluid and optionally permeable to drug at a predetermined rate, with the proviso that at least one of the first and third walls is permeable to drug at a predetermined rate, in the same general shape as the first wall; (f) placing the third wall over the drug with its perimet-er in general registry with the outer perimeter of the second wall and its periphery contacting said second wall; and (g) sealing the first and third walls to the second wall.

10. A process in accordance with claim 9 wherein the first and third walls are heat sealed to the second wall.

11. A process in accordance with claim 9 wherein the second wall is formed of a cold setting adhesive polymeric material and the first and third walls are heat sealed to the second wall at 5°C to 50°C.

12. A process in accordance with claim 9 wherein the second wall is formed of a hot setting adhesive polymeric material and the first and third walls are heat sealed to the second wall at 50°C to 250°C.

13. A process in accordance with claim 9 wherein the first and second walls are formed from polymeric materials permeable to the drug at different, predetermined rates.

14. A process in accordance with claim 9 wherein the second wall is of a color which distinguishes it from the first and third walls.