|Publication number||US3618604 A|
|Publication date||9 Nov 1971|
|Filing date||9 Jun 1969|
|Priority date||9 Jun 1969|
|Publication number||US 3618604 A, US 3618604A, US-A-3618604, US3618604 A, US3618604A|
|Inventors||Ness Richard A|
|Original Assignee||Alza Corp|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (3), Referenced by (139), Classifications (7)|
|External Links: USPTO, USPTO Assignment, Espacenet|
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
 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
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3220960 *||21 Dec 1960||30 Nov 1965||Wichterle Otto||Cross-linked hydrophilic polymers and articles made therefrom|
|US3339546 *||13 Dec 1963||5 Sep 1967||Squibb & Sons Inc||Bandage for adhering to moist surfaces|
|US3416530 *||2 Mar 1966||17 Dec 1968||Richard A. Ness||Eyeball medication dispensing tablet|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3710796 *||14 May 1971||16 Jan 1973||C Neefe||Corneal drug delivery method|
|US3811444 *||27 Dec 1972||21 May 1974||Alza Corp||Bioerodible ocular device|
|US3826258 *||7 Feb 1972||30 Jul 1974||Abraham S||Gradual release medicine carrier|
|US3828777 *||8 Nov 1971||13 Aug 1974||Alza Corp||Microporous ocular device|
|US3868445 *||16 Nov 1973||25 Feb 1975||Pharmacia Ab||Dosage unit containing a substance showing a topical effect on the eye, and a method of preparing same|
|US3870791 *||22 Jan 1974||11 Mar 1975||Haddad Heskel M||Solid state ophthalmic medication delivery method|
|US3914402 *||14 Jun 1973||21 Oct 1975||Alza Corp||Ophthalmic dosage form, for releasing medication over time|
|US3926188 *||14 Nov 1974||16 Dec 1975||Alza Corp||Laminated drug dispenser|
|US3957049 *||22 May 1975||18 May 1976||Neefe Charles W||Rechargeable drug delivery method|
|US3960150 *||15 Sep 1975||1 Jun 1976||Alza Corporation||Bioerodible ocular device|
|US3961628 *||21 Apr 1975||8 Jun 1976||Alza Corporation||Ocular drug dispensing system|
|US3981303 *||31 Jul 1975||21 Sep 1976||Alza Corporation||Bioerodible ocular device|
|US3985897 *||14 Nov 1974||12 Oct 1976||Mead Johnson & Company||Ocular hypotensive process employing dextrorotatory sulfonamidophenethanolamines|
|US3986510 *||1 Aug 1975||19 Oct 1976||Alza Corporation||Bioerodible ocular device|
|US3993071 *||24 Jul 1975||23 Nov 1976||Alza Corporation||Bioerodible ocular device|
|US3993073 *||3 Mar 1975||23 Nov 1976||Alza Corporation||Novel drug delivery device|
|US3995635 *||4 Nov 1974||7 Dec 1976||Alza Corporation||Ocular insert|
|US4008719 *||2 Feb 1976||22 Feb 1977||Alza Corporation||Osmotic system having laminar arrangement for programming delivery of active agent|
|US4014334 *||2 Feb 1976||29 Mar 1977||Alza Corporation||Laminated osmotic system for dispensing beneficial agent|
|US4116241 *||15 Dec 1976||26 Sep 1978||Alza Corporation||Osmotic system with laminated wall comprising structurally different semipermeable lamina|
|US4144317 *||21 Sep 1977||13 Mar 1979||Alza Corporation||Device consisting of copolymer having acetoxy groups for delivering drugs|
|US4177256 *||29 Nov 1977||4 Dec 1979||Alza Corporation||Osmotic bursting drug delivery device|
|US4190642 *||11 May 1979||26 Feb 1980||Alza Corporation||Ocular therapeutic system for dispensing a medication formulation|
|US4281654 *||7 Apr 1980||4 Aug 1981||Alza Corporation||Drug delivery system for controlled ocular therapy|
|US4304226 *||3 Mar 1980||8 Dec 1981||The Procter & Gamble Company||Vaginal contraceptive|
|US4344431 *||4 Aug 1980||17 Aug 1982||University Of Delaware||Polymeric article for dispensing drugs|
|US4660546 *||7 Nov 1984||28 Apr 1987||Robert S. Herrick||Method for treating for deficiency of tears|
|US4959217 *||22 May 1986||25 Sep 1990||Syntex (U.S.A.) Inc.||Delayed/sustained release of macromolecules|
|US5054948 *||30 Jul 1990||8 Oct 1991||Terumo Kabushiki Kaisha||Liquid applicator|
|US5185152 *||13 Aug 1991||9 Feb 1993||Peyman Gholam A||Method and apparatus for controlled release drug delivery to the cornea and anterior chamber of the eye|
|US5378475 *||21 Feb 1991||3 Jan 1995||University Of Kentucky Research Foundation||Sustained release drug delivery devices|
|US5660851 *||5 Jun 1995||26 Aug 1997||Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem||Ocular inserts|
|US5902598 *||28 Aug 1997||11 May 1999||Control Delivery Systems, Inc.||Sustained release drug delivery devices|
|US5928662 *||25 Jul 1997||27 Jul 1999||Phillips; Andrew F.||Ocular drug delivery device|
|US6123957 *||16 Jul 1997||26 Sep 2000||Jernberg; Gary R.||Delivery of agents and method for regeneration of periodontal tissues|
|US6196993||19 Apr 1999||6 Mar 2001||Eyelab Group, Llc||Ophthalmic insert and method for sustained release of medication to the eye|
|US6375972||26 Apr 2000||23 Apr 2002||Control Delivery Systems, Inc.||Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof|
|US6756049||17 Dec 2001||29 Jun 2004||Bausch & Lomb Incorporated||Sustained release drug delivery devices|
|US6756058||27 Dec 2001||29 Jun 2004||Bausch & Lomb Incorporated||Sustained release drug delivery devices with multiple agents|
|US6964781||27 Dec 2001||15 Nov 2005||Bausch & Lomb Incorporated||Sustained release drug delivery devices with prefabricated permeable plugs|
|US6991808||23 Jan 2002||31 Jan 2006||Bausch & Lomb Inc.||Process for the production of sustained release drug delivery devices|
|US7181287||24 Jul 2002||20 Feb 2007||Second Sight Medical Products, Inc.||Implantable drug delivery device|
|US7404825||5 Jun 2002||29 Jul 2008||Herrick Ii Robert S||Implant capable of forming a differential image in an eye|
|US7527621||16 Aug 2006||5 May 2009||Second Sight Medical Products, Inc.||Implantable drug delivery device|
|US7563255||2 May 2002||21 Jul 2009||Massachusetts Eye And Ear Infirmary||Implantable drug delivery device and use thereof|
|US7985208 *||18 Sep 2008||26 Jul 2011||Oasis Research LLC||Ring shaped contoured collagen shield for ophthalmic drug delivery|
|US8133501||28 Feb 2003||13 Mar 2012||Boston Scientific Scimed, Inc.||Implantable or insertable medical devices for controlled drug delivery|
|US8167855||25 Aug 2004||1 May 2012||Vista Scientific Llc||Ocular drug delivery device|
|US8252307||8 Jan 2010||28 Aug 2012||Psivida Us, Inc.||Method for treating and/or preventing retinal diseases with sustained release corticosteroids|
|US8277830||4 Oct 2011||2 Oct 2012||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8287504||22 Jul 2010||16 Oct 2012||Vista Scientific Llc||Ocular drug delivery device|
|US8298578||4 Oct 2011||30 Oct 2012||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8399006||29 Jan 2010||19 Mar 2013||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8414912||11 Dec 2009||9 Apr 2013||Massachusetts Institute Of Technology||Contact lens drug delivery device|
|US8486052||27 Dec 2010||16 Jul 2013||The Johns Hopkins University School Of Medicine||Reservoir device for intraocular drug delivery|
|US8574613||19 Jan 2010||5 Nov 2013||Psivida Us, Inc.||Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof|
|US8574659||15 Jan 2010||5 Nov 2013||Psivida Us, Inc.||Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof|
|US8623395||5 Aug 2011||7 Jan 2014||Forsight Vision4, Inc.||Implantable therapeutic device|
|US8679078||17 Sep 2012||25 Mar 2014||Vista Scientific Llc||Ocular drug delivery device|
|US8685427||31 Jul 2002||1 Apr 2014||Boston Scientific Scimed, Inc.||Controlled drug delivery|
|US8691264||24 Feb 2012||8 Apr 2014||Boston Scientific Scimed, Inc.||Implantable or insertable medical devices for controlled drug delivery|
|US8715712||28 Nov 2012||6 May 2014||Forsight Vision5, Inc.||Ocular insert apparatus and methods|
|US8765166||22 Jul 2013||1 Jul 2014||Novaer Holdings, Inc.||Drug delivery devices for delivery of ocular therapeutic agents|
|US8795712||7 May 2013||5 Aug 2014||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8808727||15 Mar 2013||19 Aug 2014||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8821457||3 Aug 2011||2 Sep 2014||Johnson & Johnson Vision Care, Inc.||Punctal plug containing drug formulation|
|US8871241||13 Nov 2003||28 Oct 2014||Psivida Us, Inc.||Injectable sustained release delivery devices|
|US8894602||2 Aug 2011||25 Nov 2014||Johnson & Johnson Vision Care, Inc.||Punctal plugs with directional release|
|US8905963||7 May 2013||9 Dec 2014||Forsight Vision4, Inc.||Injector apparatus and method for drug delivery|
|US8920826||6 Jan 2006||30 Dec 2014||Boston Scientific Scimed, Inc.||Medical imaging reference devices|
|US8939948||14 Sep 2012||27 Jan 2015||Forsight Vision5, Inc.||Ocular insert apparatus and methods|
|US9005649||14 Jul 2010||14 Apr 2015||Board Of Regents, The University Of Texas System||Methods for making controlled delivery devices having zero order kinetics|
|US9033911||5 Aug 2011||19 May 2015||Forsight Vision4, Inc.||Injector apparatus and method for drug delivery|
|US9066779||3 Jan 2014||30 Jun 2015||Forsight Vision4, Inc.||Implantable therapeutic device|
|US9102105||13 Sep 2012||11 Aug 2015||Vista Scientific Llc||Method for forming an ocular drug delivery device|
|US9180046||15 Jul 2013||10 Nov 2015||The Johns Hopkins University School Of Medicine||Reservoir device for intraocular drug delivery|
|US9192579||18 Oct 2013||24 Nov 2015||Psivida Us, Inc.||Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof|
|US9301874||1 Mar 2012||5 Apr 2016||Johnson & Johnson Vision Care, Inc.||Punctal plugs for controlled release of therapeutic agents|
|US9417238||14 Nov 2013||16 Aug 2016||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US9421126||1 Jun 2011||23 Aug 2016||Forsight Vision5, Inc.||Anterior segment drug delivery|
|US9474756||6 Aug 2015||25 Oct 2016||Forsight Vision4, Inc.||Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof|
|US9492315||5 Aug 2011||15 Nov 2016||Forsight Vision4, Inc.||Implantable therapeutic device|
|US9522082||3 Mar 2016||20 Dec 2016||The Johns Hopkins University||Reservoir device for intraocular drug delivery|
|US9526654||27 Mar 2014||27 Dec 2016||Forsight Vision4, Inc.||Ophthalmic implant for delivering therapeutic substances|
|US20020106395 *||27 Dec 2001||8 Aug 2002||Brubaker Michael J.||Sustained release drug delivery devices with prefabricated permeable plugs|
|US20020110635 *||23 Jan 2002||15 Aug 2002||Brubaker Michael J.||Process for the production of sustained release drug delivery devices|
|US20020188282 *||24 Jul 2002||12 Dec 2002||Robert Greenberg||Implantable drug delivery device|
|US20020198453 *||5 Jun 2002||26 Dec 2002||Herrick Family Limited Partnership||Implant capable of forming a differential image in an eye and methods of inserting and locating same|
|US20030021828 *||25 Sep 2002||30 Jan 2003||Control Delivery Systems||Method for treating and/or preventing retinal diseases with substained release corticosteroids|
|US20040034357 *||23 Apr 2003||19 Feb 2004||University Of Massachusetts, A Massachusetts Corporation||Controlled release implantable devices|
|US20040208909 *||12 May 2004||21 Oct 2004||Brubaker Michael J||Sustained release drug delivery devices|
|US20050027312 *||9 Aug 2002||3 Feb 2005||Andreas Hahn||Balloon occlusion device|
|US20060062826 *||14 Nov 2005||23 Mar 2006||Brubaker Michael J||Process for the production of sustained release drug delivery devices|
|US20060134176 *||21 Dec 2005||22 Jun 2006||Bausch & Lomb Incorporated||Pharmaceutical delivery system and method of use|
|US20060198892 *||22 Feb 2006||7 Sep 2006||Ellis Jeanne Y||Polymeric systems for controlled drug therapy|
|US20060270968 *||31 Jul 2006||30 Nov 2006||Robert Greenberg||Transretinal implant and method of manufacture|
|US20070026048 *||16 Aug 2006||1 Feb 2007||Robert Greenberg||Implantable drug delivery device|
|US20070112318 *||25 Aug 2004||17 May 2007||Leahy Charles D||Ocular drug delivery device|
|US20070135914 *||30 Nov 2006||14 Jun 2007||Herrick Robert S Ii||Implant capable of forming a differential image in an eye and methods of inserting and locating same|
|US20070190111 *||24 Apr 2007||16 Aug 2007||Govemment Of The U.S.A, Represented By The Secretary, Department. Of Health And Human||Ocular therapeutic agent delivery devices and methods for making and using such devices|
|US20070299515 *||30 Nov 2006||27 Dec 2007||Herrick Robert S Ii||Implant capable of forming a differential image in an eye and methods of inserting and locating same|
|US20080086101 *||20 Dec 2006||10 Apr 2008||David Freilich||Ophthalmic insert|
|US20080171072 *||9 Aug 2007||17 Jul 2008||Frank Burczynski||Ocular inserts containing apomorphine|
|US20090004244 *||27 Jun 2007||1 Jan 2009||Orilla Werhner C||Iris design as a drug depot for zonal drug delivery by contact lens|
|US20090004245 *||28 Jun 2007||1 Jan 2009||Orilla Werhner C||Use of an iris simulated layer to allow aesthetic appearance drug loaded contact lens|
|US20090162417 *||17 Dec 2008||25 Jun 2009||Cook Incorporated||Drug eluting ocular conformer|
|US20100069857 *||18 Sep 2008||18 Mar 2010||Oasis Research LLC||Ring Shaped Contoured Collagen Shield For Ophthalmic Drug Delivery|
|US20100168073 *||8 Jan 2010||1 Jul 2010||Paul Ashton||Method for treating and/or preventing retinal diseases with sustained release corticosteroids|
|US20100178315 *||8 Dec 2009||15 Jul 2010||Vista Scientific Llc||Polymeric systems for controlled drug therapy|
|US20100239637 *||11 Dec 2009||23 Sep 2010||Massachusetts Institute Of Technology||Contact lens drug delivery device|
|US20100272777 *||28 Dec 2009||28 Oct 2010||The Government Of The United States Of America, As Represented By The Secretary,||Ocular therapeutic agent delivery devices and methdos for making and using such devices|
|US20100331796 *||22 Jul 2010||30 Dec 2010||Vista Scientific Llc||Ocular drug delivery device|
|USB520277 *||4 Nov 1974||17 Feb 1976||Title not available|
|DE2243986A1 *||7 Sep 1972||29 Mar 1973||Alza Corp||Biologisch abbaubarer augeneinsatz zur verabreichung eines arzneimittels|
|EP0212959A2 *||15 Aug 1986||4 Mar 1987||BAUSCH & LOMB INCORPORATED||Sustained-release formulation containing an amin acid polymer with a lower alkyl (C1-C4) polar solvent|
|EP0212959A3 *||15 Aug 1986||1 Jun 1988||Bausch & Lomb Incorporated||Sustained-release formulation containing an amin acid polymer with a lower alkyl (c1-c4) polar solvent|
|EP0219207A3 *||15 Aug 1986||1 Jun 1988||Bausch & Lomb Incorporated||Sustained-release formulation comprising a hydrophobic polymer system|
|EP0219208A2 *||15 Aug 1986||22 Apr 1987||BAUSCH & LOMB INCORPORATED||Substained-release formulation containing an amino acid polymer|
|EP0219208A3 *||15 Aug 1986||1 Jun 1988||Bausch & Lomb Incorporated||Substained-release formulation containing an amino acid polymer|
|EP0411578A1 *||31 Jul 1990||6 Feb 1991||Terumo Kabushiki Kaisha||Liquid applicator|
|EP0863729A1 *||26 Sep 1996||16 Sep 1998||Control Delivery Systems, Inc.||Implantable controlled release device to deliver drugs directly to an internal portion of the body|
|EP0863729B1 *||26 Sep 1996||8 Dec 2004||Control Delivery Systems, Inc.||Implantable controlled release device to deliver drugs directly to an internal portion of the body|
|EP1982701A2||19 Apr 2001||22 Oct 2008||pSivida Inc||Sustained Release Drug Delivery Devices, Methods of Use, and Methods of Manufacturing Thereof|
|EP2633840A2||28 Feb 2013||4 Sep 2013||Johnson & Johnson Vision Care, Inc.||Punctal plug with energized containment array|
|WO1984004680A1 *||25 May 1983||6 Dec 1984||Alcon Lab Inc||Ophthalmic gel|
|WO1984004681A1 *||25 May 1983||6 Dec 1984||Alcon Lab Inc||Ophthalmic solution|
|WO1993019707A1 *||2 Apr 1992||14 Oct 1993||Bausch & Lomb Incorporated||Ophthalmic article|
|WO2000062760A1||7 Apr 2000||26 Oct 2000||Eyelab Group, Llc||Ophthalmic insert and method for sustained release of medication to the eye|
|WO2002064071A1 *||13 Feb 2002||22 Aug 2002||The Lions Eye Institute Of Western Australia||Device and method for anterior segment drug delivery|
|WO2003096876A2 *||3 Jan 2002||27 Nov 2003||Sommer Phillipe L||Continuously operational diagnostic device|
|WO2003096876A3 *||3 Jan 2002||25 Mar 2004||Phillipe L Sommer||Continuously operational diagnostic device|
|WO2010093873A2||12 Feb 2010||19 Aug 2010||Incept, Llc||Drug delivery through hydrogel plugs|
|WO2011123180A1||2 Apr 2011||6 Oct 2011||Praful Doshi||Medical devices including medicaments and methods of making and using same|
|WO2012033730A2||6 Sep 2011||15 Mar 2012||Johnson & Johnson Vision Care, Inc.||Punctal plug containing drug formulation|
|WO2012037330A1||15 Sep 2011||22 Mar 2012||Johnson & Johnson Vision Care, Inc.||Punctal plugs with directional release|
|WO2012082486A1||7 Dec 2011||21 Jun 2012||Johnson & Johnson Vision Care, Inc.||Punctal plug with drug core retention features|
|WO2012154427A1||27 Apr 2012||15 Nov 2012||Johnson & Johnson Vision Care, Inc.||Punctal plugs for controlled release of therapeutic agents|
|WO2015071427A1||14 Nov 2014||21 May 2015||Eyed Pharma||Eye device|
|WO2015164563A1||23 Apr 2015||29 Oct 2015||Johnson & Johnson Vision Care, Inc.||Method and ophthalmic device with active agent release system|
|International Classification||A61F9/00, A61K9/00|
|Cooperative Classification||A61F9/0017, A61K9/0051|
|European Classification||A61F9/00B2, A61K9/00M16B|