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Publication numberUS3618604 A
Publication typeGrant
Publication date9 Nov 1971
Filing date9 Jun 1969
Priority date9 Jun 1969
Publication numberUS 3618604 A, US 3618604A, US-A-3618604, US3618604 A, US3618604A
InventorsNess Richard A
Original AssigneeAlza Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Ocular insert
US 3618604 A
Images(1)
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Description  (OCR text may contain errors)

United States Patent Inventor Richard A. Ness Fergus Falls, Minn. App]. No. 831,761 Filed June 9, 1969 Patented Nov. 9, 1971 Assignee Alza Corporation OCULAR INSERT 21 Claims, 2 Drawing Figs. US. Cl. 128/260, 128/156 lnt .Cl ..A6lm 31/00 Field 01 Search 128/260, 296, 156

[56] References Cited UNITED STATES PATENTS 3,220,960 1 1/ 1965 Wichterle 260/25 3,339,546 9/1967, Chen 128/156 3,416,530 12/1968 Ness 128/260 Primary Examiner-Robert W. Michell Assistant ExaminerR. P. Dyer Attorney-Steven D. Goldby ABSTRACT: Drug-dispensing ocular insert is comprised of a flexible body of polymeric material that is insoluble in tear liquid and has an imperforate surface. The polymeric material contains a drug which is dispensed to the eye in a therapeuti cally effective amount by diffusion through the polymeric material. The ocular insert is adapted for insertion in the culde-sac of the conjunctiva between the sclera of the eyeball and the lower lid, to be held in place against the eyeball by the pressure of the lid.

PATENTEUNUV 91971 3.618504 mvsmron RICHARD A. NESS BACKGROUND OF THE INVENTION This invention relates to an ocular insert for dispensing drugs to the eye over a prolonged period of time.

At the present time, diseases of the eye are treated by applying ophtahalmic drugs in liquid or ointment form. To be effective in many cases, the application of drug should be substantially continuous. Such continuous delivery of drug is not obtained through the use of liquid or ointment dosage forms, even though they be applied at intervals during the day and night. Periodic application of these dosage forms results in the eye receiving a massive, but unpredictable, amount of drug at the time of application but the drug is washed away rapidly by tears, leaving the eye without medication until the nextapplication. Ointment dosage forms are presently available only in unsterilized form and this too presents a problem.

At a very early time, drugs were dissolved or'dispersed in a water-soluble gel of gylcerinated gelatin that was shaped to the form of a lamella or eye disk. These lamellae were applied to the inner surface of the eyelid to supply drug to the eye. In use, the glycerinated gelatin vehicle liquid, producing the fonns. Lamellae were same type of effect as liquid dosage not a sustained-release dosage form. To my knowledge, they are not used in this country, although they may be' used to a small extent in Europe. Further information on these water-soluble dosage forms can be found in Remingtons Pharmaceutical Sciences, Xlll, pages 547-8 (Mack Publishing Co., Easton, Pa. 1965); Fishbum, An Introduction to Pharmaceutical Formulation, page 116 (Pergamon Press Ltd, New York Cit NY. 1965); and U.S. Pat. No. 273,410,Mar.6, 1883.

U.S. Pat. No. 3,416,530, granted Dec. 17, 1968, and assigned to the assignee of this invention, is directed to my invention of a drug-dispensing ocular insert that truly acts as a depot or drug reservoir, retaining and slowly releasing drug to the eye for prolonged periods of time. Such ocular inserts are fabricated of flexible polymeric materials that are biologically inert, nonallergenic, and insoluble in tear liquid. To initiate the therapeutic program, the ocular insert is placed in the culde-sac of the conjunctiva between the sclera of the eyeball and the lid. Since the polymeric material from which the ocular insert is formed is insoluble in tear liquid it retains its integrity and remains intact during the course of therapy, acting as a reservoir to continuously release drug to the eye and sur rounding tissues at a rate which is not affected by dissolution or erosion of the polymeric material. On termination of the therapeutic program, the ocular insert is removed from the cul-de-sac. Thus, a single such ocular insert provides the complete ophthalmic dosage regime for a particular time period, on the order of 24 hours or longer. Frequent repeated applications, as is necessary with liquids, ointments, or watersoluble lamellae, often requiring awakening the patient during the night, are avoided.

To provide for release of ophthalmic drug from the polymeric body of the ocular insert, U.S. Pat. No. 3,416,530 describes using polymeric materials which are perforated with capillary openings. While these capillary openings are effective to release drug to the eye, they add considerable complexity to the manufacture of ocular inserts; for its is difficult to control the size of these openings in large-scale manufacturing using various polymers.

The best mode contemplated for practicing the invention of U.S. Pat. 3,416,530, was, at the time the patent application maturing to that patent was filed, to place the ocular insert under the upper eyelid in generally radically spaced relation to the cornea of the eyeball and in the path of flow of tears from the associated lachrymal gland. However, the eye has a tendency to roll upwardly during sleeping a process known as Bell's Phenomenon, which may cause discomfort to some persons if the ocular insert is under the upper lid.

dissolved'rapidly in tear 2 SUMMARY OF THE INVENTION dispensing ocular insert which delivers drugs to the eye at a controlled rate, that is not number of perforations or ocular insert. 7

Still another object of this invention dependent upon the size and pores in the polymeric body of the is to provide a drugdispensing ocular insert which is comfortable to wear for long resides in a drug-dispensing ocular insert periods and does not cause discomfort during sleeping and normal daily wear. In accomplishing these objects, one feature of this invention to deliver during to the eye over aprolonged period of time, comprising a flexible ody of polymeric material insoluble in tear liquid and having an imperforate surface, the body containing a drugwhichis dispensed to the eye in a therapeutically effective amount by diffusion through the polymeric material. The ocular insert of this invention is adapted for insertion in the cul-de-sac of the conjunctiva betweenthe sclera of the eyeball and the lower lid, to be held in place against the eyeball by the pressure of the lid.

Other objects features and advantages of the invention will become more apparent from the following description of the invention and from the claims.

.Belgian Pat. No. 701,813),

DETAILED DESCRlPTlON or THE INVENTION In accordance with this invention, insert is designed for placement and eyelid and is fabricated of a perforate surface, that therethrough.

Polymeric materials used in forming the ocular insert are flexible, biologically inert, insoluble in tear liquid, and nonallergenic. It is important that thepolyrneric material be capable of transferring the drug through its unbrokenwalls by the diffusion of drug or drug solution therethrough. By utilizing the mechanism of difiusion to dispense drug to the eye, the rate of drug release can be controlled with precision and reproducibility. In each case, selection of the polymeric material is dependent on the particular drug and drug form to be used in the device. Exemplary materials forfabricating the ocular insert include hydrophobic polymers such as plasticized or unplasticized polyvinylchloride, plasticized nylon, unplasticized soft nylon, plasticized polyethylene terephtahalate, and silicone rubber; and hydrophilic polymers such as the hydrophilic hydrogels of esters of acrylic and methacrylic acid (as described in U.S. Pat. Nos. 2,976,576 and 3,220,960 and modified collagen, cross-linked hydrophilic polyether gels (as described in U.S. Pat. No. 3,419,006), cross-linked polyvinylalcohol, and cross-linked partially hydrolyzed polyvinylacetate. When plasticizers are used to impart flexibility to the polymer, various plasticizers kriown to the art can be employed, such as long-chain fatty amides, higher alcohols, and dioctyl phthalate.

Those skilled in the art will appreciate that many of the hydrophilic polymers suitable for use in this invention absorb forming a hydrogel therewith. Tear liquid entering to form the swollen hydrogel molecules dissolves the drug within the polymeric body, and the resulting drug solution then diffuses outwardly from: the the hydrogel structure. Therefore, as used in this specification and the appended claims, the term diffusion? refers to the movement of a drug through an imperforate polymeric body, as well as to the movement of adrug solution through an imperforate body. Use of the expression insoluble in tear liquidf to refer to suitable polymeric materials, means that the polymeric materials do not dissolve and erode as a result of the action of tear liquid, but may absorb tear liquid, forming a swollen hydrogel.

a drug-dispensing ocular retention under the lower polymeric material, having an imwill release drug by diffusion Any of the drugs used to treat the eye and surrounding tissues can be incorporated in the ocular insert of this invention. Also, it is practical to use the eye and surrounding tissues as a point of entry for systemic drugs that enter circulation in the blood stream and produce a phannacologic response at a site remote from the point of application of the ocular insert. Thus, drugs which will pass through the eye or the tissue surrounding the eye to the bloodstream, but which are not used in therapy of the eye itself, can be incorporated in the ocular insert.

Suitable drugs for use in therapy of the eye with the ocular insert include, without limitation: Anti-infectives: such as antibiotics, including tetracycline, chlortetracycleine, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin; sulfonamides, including sulfacetamide, sulfamethizole, and sulfisoxazole; antivirals, including idoxuridine; and other anti-infectives including nitrofurazone and sodium propionate; Antiallergenics such as antazoline, methapyrilene, chlorpheniramine, pyrilamine and prophenpyridamine; Anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 2l-phosphate, fluocinolone, medrysone, prednisolone, prednisolone ZI-phosphate and prednisolone acetate; Decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; Miotics and anticholinesterases such as pilocarpine, eserine salicylate, carbachol, diisopropyl flur'ophosphate, phospholine iodide, and demecarium bromide; Mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine and Sypathomimetics such as epinephrine. Drugs can be in various forms, such as uncharged molecules, components of molecular complexes, or nonirritating, pharmacologically acceptable salts, such as hydrochloride, hydrobromide, sulfate phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc. Furthermore, simple derivatives of the drugs (such as ethers, esters, amides, etc.,) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, etc. can be employed. The amount of drug incorporated in the ocular insert varies widely, depending on the particular drug, the desired therapeutic effect, and the time span for which the ocular insert will be used. Since the ocular insert is intended to provide the complete dosage regime for eye therapy for but a particular time span, such as 24 hours, there is no critical upper limit on the amount of drug incorporated in the device. For when the device is removed and disposed of it makes little difference whether any drug remains in the device. The lower limit will depend on the activity of the drug and its capability of being released from the device. Thus it is not practical to define a range for the therapeutically effective amount of drug incorporated into the device. However, typically, from I microgram to l milligram of drug is incorporated in the ocular insert.

In each case, the polymeric material used to form the ocular insert is chosen for its compatibility with a particular drug and its capability of releasing that drug by diffusion at an appropriate rate over a prolonged period of time. Specific, but nonlimiting, examples of combinations of drugs and polymers for use in forming the ocular insert are: (l) chloramphenicol incorporated into polyethylene terephthalate plasticized with higher alcohols; (2) promethazine trichloroacetate incorporated into polyvinylchloride plasticized with dioctylphthalate; (3) chloramphenicol dispersed throughout polydimethylsiloxane rubber; (4) pilocarpine or pilocarpine perfluorobutyrate incorporated into polyvinylchloride plasticized with dioctylsebecate; and (5) dexamethasone incorporated into nylon-plasticized with higher alcohols.

The ocular insert can be fabricated in any convenient shape for comfortable retention in the cul-de-sac. It is important, however, that the device have no sharp, jagged, or rough edges which can irritate the sensitive tissues of the eye. Thus the marginal outline of the ocular insert can be ellipsoid, beanshaped, rectangular, etc. In cross section, in can be concavoconvex, rectangular, etc. As the ocular insert is flexible and, in used, will assume essentially the configuration of the scleral curvature, the original shape of the device is not of controlling importance. Dimensions of the device can vary widely. The lower limit on the size of the device is governed by the amount of the particular drug to be applied to the eye and surrounding tissues to elicit the desired pharmacologic response, as well as by the smallest sized device which conveniently can be inserted and removed from the eye. The upper limit on the size of the device is governed by the limited space within the culde-sac that conveniently and comfortably can be filled with an ocular insert. Typically, the ocular insert is 4 to 20 millimeters in length, l to 12 millimeters in width, and 0.1 to l millimeter in thickness. Preferably it is ellipsoidal in shape and about 6 X4 0.5 millimeters in size.

The ocular insert can be a polymeric matrix with the drug dispersed therethrough or can be a sealed container with walls of polymeric material and having the drug in an interior chamber thereof. One such container has a circular or ellipsoidal cross section and is tapered at the ends. Drug can be incorporated in the ocular insert in many ways. When the ocular insert is in the form of a container, any of the encapsulation, bonding, and coating techniques conventionally used in the art can be employed. When the ocular insert is a solid matrix with the drug dispersed therethrough, it can be fabricated by adding the drugs to the monomers prior to polymerization; adding the drug to the polymer in liquid form, molding and curing; or by impregnating the polymeric material, either before or after shaping to the form of the ocular insert, with the drug.

Referring particularly to FIG. 1 and 2, to use the ocular insert 10 (shown by dot and dash lines in FIG. 1), it is placed in the cul-de-sac ll of the conjunctiva 12 between sclera 13 of the eyeball l4 and the lower lid 15. The pressure of the lower lid 15 maintains the ocular insert 10 in place. With the ocular insert 10 under the lower lid 15, the device is comfortable to the wearer and does not contact the cornea 16 during sleeping nor during normal ocular motion. Once in place, the ocular insert 10 functions as a drug reservoir gradually releasing drug to the eye and surrounding tissue. Drug 17 leaving the ocular insert by diffusion is transported to the eyeball 14 by the flow of tear liquid and by the blinking action of the eyelids. By use of the ocular insert, the eye is continuously bathed with drug 17 over a particular time span. Normally, the ocular insert 10 will be retained in place for a period of 24 hours, thereby supplying the complete dosage regime for eye therapy over that period of time. During the course of use, the polymeric body 18 of the ocular insert does not dissolve or erode in tear liquid and a predictable and reproducible dosage regime is provided.

In a specific example of the manufacture of an ocular insert the invention, liquid polydimethylsiloxane (dow Corning Silastic 382) is mixed with chloramphenicol antibiotic. After uniformly mixing the antibiotic with the unvulcanized silicone rubber, stannous octoate catalyst (0.5 percent by weight) is added to the mixture is poured into a mold having an ellipsoidal cavity 6 millimeters by 4 millimeters by 0.5 millimeter to cure the silicone rubber at room temperature. The resulting ocular insert formed of silicone rubber contains 0.5 milligram of chloramphenicol. When inserted in the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lower lid, the ocular insert is effective to deliver to the eye the dose of chloramphenicol antibiotic required for 24 hours of treatment of infection. After that period of time, the ocular insert, with its dimensions unchanged, is removed from the cul-desac and an identical insert placed in its stead to continue the therapeutic program for an additional 24 -hour period.

Thus, the improved ocular insert of this invention offers many advantages. As it is formed of a polymeric material, insoluble in tear liquid, the ocular insert does not dissolve or erode in tear liquid during the course of therapeutic program. This permits the therapeutic program to be precisely controlled and the release of drug predicted with accuracy. That the ocular insert releases drug by diffusion is most important, since this too provides for close control over the rate of drug release from the polymer.

While there have been described and pointed out the fundamental novel features of the invention as applied to the preferred embodiment, those skilled in the art will appreciate that various modifications, changes, and omissions in the ocular insert illustrated and described can be made without departing from the spirit of the invention. It is the intention, therefore, to be limited only by the scope of the following claims.

What is claimed is:

l. A medication-dispensing tablet for a human eyeball, said tablet comprising a reservoir of drug formulation confined within a flexible, imperforate and continuous-surfaced body of nonallergenic polymeric material which is insoluble in tear liquid, said body being formed of a drug-release rate-controlling polymer to continuously meter the flow of drug by diffusion from the reservoir to the eye at a controlled, predetermined and reproducible rate over a prolonged period of time, said body being adapted for insertion into the cul-de-sac of the conjunctiva between the sclera of the eyeball and eyelid, to be held in place against the eyeball by the pressure of the lid, and said body having a marginal outline and cross section adapted to assume essentially the configuration of the scleral curvature; said drug being capable of transport through the unbroken walls of said body by diffusion and said body being so constructed and arranged that, when applied to the eyeball, to dispense said drug leaving said body by diffusion is transported to the eyeball by the flow of tears and by the blinking action of the eyelids.

2. The medication-dispensing tablet as defined by claim 1, wherein the reservoir of drug formulation is comprised of a sealed container with walls of said polymeric material and said drug is contained in an interior chamber thereof.

3. The medication-dispensing tablet as defined by claim 2, wherein said polymeric material is selected from the group consisting of plasticized or unplasticized polyvinyl chloride, plasticized nylon, unplasticized soft nylon, plasticized polyethylene terephthalate, silicone rubber, hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

4. The medication-dispensing tablet as defined by claim 3, wherein said polymeric material is silicone rubber.

5. The medication-dispensing tablet as defined by claim 3, wherein said polymeric material is a hydrophilic hydrogel of an ester of acrylic or methacrylic acid.

6. The medication-dispensing tablet as defined by claim 1, wherein the reservoir of drug formulation is comprised of a matrix of the drug-release ratecontrolling polymeric material, said matrix having the drug distributed therethrough.

7. The medication-dispensing tablet as defined by claim 1,

wherein said polymeric material is selected from the group consisting of plasticized unplasticized polyvinyl chloride, plasticized nylon, unplasticized soft nylon, plasticized polyethylene terephthalate, silicone rubber, hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl acetate.

8. The medication-dispensing tablet as defined by claim 7, wherein said polymeric material is silicone rubber.

9. The medication-dispensing tablet as defined by claim 7, wherein said polymeric material is a hydrophilic hydrogel of an ester of acrylic or methacrylic acid.

10. The medication-dispensing tablet as defined by claim 1, wherein said drug is an ophthalmic drug.

11. The medication-dispensing tablet as defined by claim 1, wherein said drug is a systemically active drug which will pass through the eye to the bloodstream and produce a pharmacologic response at a site remote from the eye.

vl2. The medication-dispensing tablet as defined by claim 1, wherein said drug is a systemically active drug which will pass through the tissue surrounding the eye to the bloodstream and produce a pharmacologic response at a site remote from the l3. The medication-dispensing tablet as defined by claim 1, wherein from 1 microgram to l milligram of drug is incorporated in said tablet.

14. The medication-dispensing tablet as defined by claim 1,

I wherein same is circular in cross section and tapered at its ends.

15. The medication-dispensing tablet as defined by claim 1, wherein same is ellipsoidal in cross section and tapered at its ends.

16. The medication-dispensing tablet as defined by claim I, wherein same ranges from 4 to 20 millimeters in length, l to 12 millimeters in width, and 0.1 to l millimeter in thickness.

17. The medication-dispensing tablet as defined by claim 1, wherein the drug is chloramphenicol and the polymeric material is polyethylene terephthalate.

18. The medication-dispensing tablet as defined by claim 1, wherein the drug is promethazine trichloroacetate and the polymeric material is polyvinyl chloride.

19 The medication-dispensing tablet as defined by claim 1, wherein the drug is ehloramphenicol and the polymeric material is polydimethylsiloxane rubber.

20. The medication-dispening tablet as defined by claim 1, wherein the drug is a member selected from the group consisting of pilocarpine and pilocarpine perfiuorbutyrate and the polymeric material is polyvinyl chloride.

21. The medication-dispensing tablet as defined by claim 1, wherein the drug is dexamethasone and the polymeric material is nylon-66.

K i t i UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 8, 0 Dated November 9, 1971 Inventor(s) Richard A. Ness It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 8, "ophtahalmic" should read ophthalmic-; line 20, "gylcerinated" should read -glycerinated-; line 64, "its" should read it--; line 70, "radically" should read -radially-. Column 2, line 16, "during" should read drug-; line 50, "terephtahalate" should read terephthalate.

Column 3, line 13, "chlortetracycleine" should read --chlortetracycline; line 31, "Sypathomimetics" should read Sympathomimetics-; line 35, following the word "sulfate" insert a comma; line 69, "nylon-plasticized" should read nylon-66 plasticized-; line 75, "in", second occurrence,

should read -it-. Column 4, line 2, "used" should read use-; line 31, "FIG." should read -FIGS.-; line 50, after "insert" add of-; line 51, "dow" should read Dow--; line 55, "to" should read and. Claim 1, line 12, delete the hyphen between "continuous" and "surfaced". Claim 1, line 27, insert thereto, drug-- between "drug" and "leaving".

Claim 7, line 2, insert or between "plasticized" and "unplasticized". Claim 7, line 7, after "polyvinyl delete "acetate." and insert alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.--. Claim 20, line 47, "perfluorbutyrate" should read perfluorobutyrate.

In all the claims, each occurrence, delete the hyphen between "medication" and "dispensing".

Signed and sealed this 2nd day of May 1972.

EM F'O-1050 (10-69) (SEAL) Attest:

EDWARD M.FLE'I'CHER, JR. 5055111 Li-U'l'l'SUtiJ-LLK Attesting Officer Co missioner of Patents USCOMM-DC 6O376-F69 U S GOVERNMENT PRINHNG OFFICE 1969 0-366-334

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Classifications
U.S. Classification604/294
International ClassificationA61F9/00, A61K9/00
Cooperative ClassificationA61F9/0017, A61K9/0051
European ClassificationA61F9/00B2, A61K9/00M16B