A RetroSearch Logo

Home - News ( United States | United Kingdom | Italy | Germany ) - Football scores

Search Query:

Showing content from https://patents.google.com/patent/US3630200A/en below:

US3630200A - Ocular insert - Google Patents

US3630200A - Ocular insert - Google PatentsOcular insert Download PDF Info
Publication number
US3630200A
US3630200A US831481A US3630200DA US3630200A US 3630200 A US3630200 A US 3630200A US 831481 A US831481 A US 831481A US 3630200D A US3630200D A US 3630200DA US 3630200 A US3630200 A US 3630200A
Authority
US
United States
Prior art keywords
drug
ocular insert
inner core
eye
hydrophilic
Prior art date
1969-06-09
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US831481A
Inventor
Takeru Higuchi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alza Corp
Original Assignee
Alza Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1969-06-09
Filing date
1969-06-09
Publication date
1971-12-28
1969-06-09 Application filed by Alza Corp filed Critical Alza Corp
1971-12-28 Application granted granted Critical
1971-12-28 Publication of US3630200A publication Critical patent/US3630200A/en
1988-12-28 Anticipated expiration legal-status Critical
Status Expired - Lifetime legal-status Critical Current
Links Images Classifications Definitions Landscapes Abstract

Drug dispensing ocular insert for insertion into the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid to dispense drug to the eye over a prolonged period of time is rendered more compatible with the eye and surrounding tissues by fabricating the insert of an inner core containing the drug and a soft hydrophilic outer layer.

Description

United States Patent [72] Inventor Takeru Higuchi Lawrence, Kans. [21] Appl. No. 831,481 [22] Filed June 9, 1969 [45] Patented Dec. 28, 1971 [73] Assignee ALZA Corporation [54] OCULAR INSERT 22 Claims, 2 Drawing Figs.

[52] U.S. C1 [51] lnt.Cl.. ..A61m 31/00 [50] Field 01 Search 128/260,

[56] References Cited UNITED STATES PATENTS 3,006,338 10/1961 Davies 128/156 Primary Examiner-Robert W. Michell Assistant Examiner-R. P. Dyer A!!orneySteven D. Goldby ABSTRACT: Drug dispensing ocular insert for insertion into the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid to dispense drug to the eye over a prolonged period of time is rendered more compatible with the eye and surrounding tissues by fabricating the insert of an inner core containing the drug and a soft hydrophilic outer layer.

' PATENTEDnmsmn I 31530200 Fig.2

INVENTOR.

Takeru Hiquc MAQW Attorney OCULAR INSERT BACKGROUND OF THE INVENTION This invention relates to an ocular insert for dispensing drugs to the eye and, more especially, to an ocular insert having improved compatibility with the eye and surrounding tissues.

At the present time, diseases of the eye are treated by applying ophthalmic 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 next application. Ointment dosage forms are presently available only in unsterilized form and this too presents a problem. 1

At a very early time, drugs were dissolved or dispersed in a water soluble gel of glycerinated 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 dissolved rapidly in tear liquid, producing the same type of effect as liquid dosage forms. Lamellae were 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, XIII, pages 547-8 (Mack Publishing Co., Easton, Pa. 1965); Fishburn, An Introduction to Pharmaceutical Formulation, page 1 l6 (Pergamon Press Ltd., New York City, N.Y. 1965); and U5. Pat. No. 273,410, Mar. 6, 1883.

US. Pat. No. 3,416,530, granted Dec. 17, 1968, and assigned to the assignee of this invention, is directed to the 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 surrounding 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 water soluble lamellae, often requiring awakening the patient during the night, are avoided.

The necessary characteristics for the material used to fabricate the ocular insert and obtain the desired drug metering effect are dependent on the particular drug used. With many drugs, hydrophobic polymeric materials having a relatively high affinity for the drug should be used in forming the ocular insert. Otherwise, the drug will be rapidly released from the ocular insert and the objective of continuous and sustained release defeated. However, many hydrophobic polymers having the desired drug retention and release characteristics tend to be irritating to the eye and surrounding tissues. To provide compatibility with the eye and surrounding tissues, it has been found that the surface of the ocular insert in contact with the eye and surrounding tissues should be soft and hydrophilic. Since hydrophilic materials do not have the drug retention characteristics needed for many drugs, it has been necessary at times in the past to select materials which compromise the desired comfort and tissue compatibility with the desired retention and release characteristics for the drug.

SUMMARY OF THE INVENTION Accordingly, it is an object of this invention to provide an improved ocular insert that is compatible with and nonirritating to the eye and surrounding tissues.

Another object of this invention is to provide an improved ocular insert which can retain and slowly release a wide variety of drugs to the eye.

In attaining the objects of this invention, one feature resides in a drug dispensing ocular insert comprising a flexible body containing a drug and adapted for insertion into the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid to dispense drug to the eye over a prolonged period of time. The ocular insert is rendered more compatible with the eye and surrounding tissues by comprising it of an inner core containing the drug and having an affinity therefor and a soft, hydrophilic outer layer.

Another feature of this invention resides in the ocular insert described above wherein the inner core is a hydrophobic polymer having an affinity for drugs and capable of slowly releasing such drugs to the eye over a prolonged period of time.

Other objects, features, and advantages of this invention will become more apparent from the following description when taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings FIG. I is a cross-sectional view of the ocular insert of this invention and FIG. 2 is a cross-sectional view of a modified ocular insert of this invention.

As illustrated in FIG. 1, the ocular insert 10 of this invention is comprised of an inner core II, which is a matrix having drug 12 dispersed therethrough. Surrounding inner core 11 is an outer layer I3 of a soft hydrophilic material. Drug l2 gradually difi'uses through or is leached from inner core II and passes through hydrophilic outer layer 13 to the eye and surrounding tissues.

In FIG. 2, the modified ocular insert 10 of the invention has a hollow inner core 11 having an interior chamber I4 containing drug I2. As with the other form of the ocular insert, drug 12 gradually diffuses through or is leached by tear liquid from the walls of inner core 11, passes through outer layer I3 and contacts the eye and surrounding tissues.

DETAILED DESCRIPTION OF THE INVENTION To use the ocular insert of the invention, it is inserted in the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid. While the ocular insert can be inserted under either the upper lid or the lower lid, placement of the ocular insert under the lower lid is preferred. The eye has a tendency to roll upwardly during sleeping, known as Bells Phenomenon, which may cause discomfort to some persons if the ocular insert is under the upper lid. Once in place, the ocular insert functions as a drug reservoir gradually releasing drug to the eye and surrounding tissues. Drug leaving the ocular insert, whether by diffusion through the walls of the insert or as a result of the leaching action of tear liquid, is transported to the eyeball by the flow of tear liquid or by the blinking action of the eyelids.

By use of the ocular insert, the eye is continuously bathed with drug over a particular time span. Normally, the ocular insert 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. Because the outer layer of the ocular insert is formed of a soft hydrophilic material, the device can remain in place for long periods of time without causing discomfort to the patient. This is achieved without sacrificing the necessary drug retention and release properties, since the inner core, which does not contact the eye and surrounding tissues, can be selected based on these properties.

The ocular insert can be fabricated in any convenient shape for comfortable retention in the cul-de-sac. Thus, the marginal outline of the ocular insert can be ellipsoid, beanshape, rectangular, etc. In cross section, it can be concavoconvex, rectangular, etc. As the ocular insert is flexible and, in use, will assume essentially the configuration of the cul-de-sac, 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 supplied 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 cul-de-sac that conveniently and comfortably can be filled with an ocular insert. Typically, the ocular insert is 4 to millimeters in length, 1 to 12 millimeters in width, and 0.1 to 1 millimeter in thickness.

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 pharmacologic 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 blood stream, 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 of this invention include, without limitation: Anti-infectives: such as antibiotics, including tetracycline, chlortetracycline, 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; Antiinflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone 21- phosphate, and prednisolone acetate; Decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; Miotics and anticholinesterases such as pilocarpine, eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholine iodide, and demecarium bromide; Mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; and Sympathomimetics such as epinefrine. 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. For acidic drugs, salts of metals, amines, or organic cations (e.g. quaternary ammonium) can be employed. 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 to be released by the device. However, typically, from 1 microgram to l milligram of drug is incorporated in the ocular insert.

As described and illustrated above, the inner core of the ocular insert can be a matrix with the drug dispersed therethrough or can be a hollow capsule with the drug within its interior chamber. The inner core need not be a unitary member but can be made up of discrete particles or hollow capsules which release drug by diffusion or the leaching action of tear liquid. Since the function of the inner core is to act as the reservoir for the drug, it is fabricated, in each case, of a material that provides the optimal environment for the desired depot and release characteristics for the drug being used. No compromise between the retention and release characteristics and the compatibility with the eye and surrounding tissues must be made when designing the device of this invention since the outer layer is independently selected for its eye and tissue compatibility. Suitable materials for the inner core are those flexible materials through which the drug will diffuse or be leached by the action of tear liquid at a slow rate. Exemplary materials for fabricating the inner core of the device include hydrophobic polymers such as polyvinylchloride either unplasticized or plasticized with long chain .fatty amides or other plasticizer, plasticized nylon, unplasticized soft nylon, silicone rubber, and polyethylene; and hydrophilic polymers such as the hydrophilic hydrogels of esters of acrylic and methacrylic acid (as described in U.S. Pats. Nos. 2,976,576 and 3,220,960 and Belgian Pat. No. 701,813), modified collagen, cross-linked hydrophilic polyether gels (as described in U.S. Pat. No. 3,419,006), cross-linked polyvinylalcohol, cross-linked partially hydrolyzed polyvinylacetate, cellulosic gels such as methylcellulose and hydroxyethylcellulose; and ion exchange resins, especially those with a low degree of cross-linkings. By using hydrophobic polymers as the core material, one obtains the maximum advantages from the present invention since this invention overcomes the disadvantages inherent in use of hydrophobic polymers in previously known ocular inserts.

Specific, but nonlimiting, examples of combinations of drugs and polymers for the inner core are:

1. chloramphenicol incorporated into polyethylene terephthalate plasticized with higher alcohols;

2. promethazine trichloroacetate incorporated into polyvinyl chloride plasticized with dioctylphthalate;

3. chloramphenicol dispersed throughout polydimethylsiloxane;

4. pilocarpine or pilocarpine perfluorobutyrate incorporated into polyvinyl chloride plasticized with dioctylseboate; and

5. dexamethasone incorporated into 6-6 nylon plasticized with higher alcohols.

In the ocular insert of this invention, the outer layer functions to render the device compatible with the eye and surrounding tissues and comfortable to the wearer. It should not provide a significant barrier to flow or passage of drug from the inner core to the eye and surrounding tissues. Materials used in fabricating the outer layer of the ocular insert are soft, flexible, hydrophilic, and insoluble in tear liquid. While these materials are hydrophilic and absorb water, they should not be substantially eroded or dissolved in the tear liquid. Exemplary materials include hydrophilic hydrogels of esters of acrylic and methacrylic acid (as described in U.S. Pats. Nos. 2,976,576 and 3,220,960, and Belgian Pat. No. 701,813), modified collagen, cross-linked hydrophilic polyether gels (as described in U.S. Pat. No. 3,419,006), cross-linked polyvinylalcohol, cross-linked partially hydrolyzed polyvinylacetate, and cellulosic gels such as methylcellulose and hydroxyethyl cellulose. Of course, the hydrophilic material used to form the outer layer will, in each case, have different characteristics than the material used to form the inner core of the particular ocular insert. Such hydrophilic materials are permeable to gases and liquids which is desirable in the eye since it permits free transfer of eye fluids, drugs, and oxygen. In a preferred embodiment of this invention, the inner core is also porous to liquid and gas flow to assist in the transfer of oxygen and eye fluids through the ocular insert.

The relative thickness of the inner core and the outer hydrophilic layer can vary widely and is not a limitation on the invention.

Drug can be incorporated in the inner core in many ways. When the inner core is a hollow capsule, any of the encapsulation techniques conventionally used can be employed. When the inner core is a solid matrix with the drug dispersed therethrough, the inner core can be fabricated by adding the drug to the monomers prior to polymerization; adding the drug to the polymer in liquid form, molding, and curing; or by impregnating the inner core with the drug. Thereafter, the inner core, containing the drug, can be coated with or laminated to the hydrophilic outer layer. When lamination is employed to fabricate the insert, the device may comprise a sheet of inner core material sandwiched between two sheets of outer layer material. To enhance adhesion between the layers, the inner core can be perforated or embossed.

In a specific example of the manufacture of a device of the invention, liquid polydimethylsiloxane (Dow Corning Silastic) is mixed with chloramphenicol antibiotic. After uniformly mixing the antibiotic with the unvulcanized layers, the inner core can be perforated or embossed.

In a specific example of the manufacture of a device of the invention, liquid polydimethylsiloxane (Dow Corning Silastic) 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 and the mixture is poured into a mold having a cavity 8X2X0.2 mm. to cure the silicone rubber at room temperature. The resulting silicone rubber body contains 0.5 milligram of chloramphenicol. 2-hydroxyethyl methacrylate 100 parts by weight) is mixed with tertiary butyl peroctoate (0.2 part by weight) and ethylene glycol dimethacrylate (0.2 by weight) to provide a casting syrup which is coated onto the foregoing silicone rubber body in a mold and cured at 70 C. The dimensions of the resulting ocular insert are l0 4X0.8 mm. lmmediately prior to use, the outer surface of the ocular insert is wet with water which softens the hydrophilic poly (hydroxyethyl methacrylate) outer layer forming a hydrogel thereof. When inserted in the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid, the ocular insert is effective to deliver to the eye the dose of chloramphenicol antibiotic required for 24 hours of treatment of infection. The soft hydrophilic outer layer is compatible with the eye and surrounding tissues and produces no irritation or discomfort.

Thus, the improved ocular insert of this invention offers many advantages. The inner core material, which functions as the drug reservoir to retain and release the drug, can be chosen so as to produce the optimum environment for the drug. In selecting this material, one need not consider its compatibility with the eye and surrounding tissues since the ocular insert includes an external layer that is soft, flexible, hydrophilic, and compatible with the eye and surrounding tissues.

While there have been shown and 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. In a drug dispensing ocular insert comprising a flexible body containing a drug and adapted for insertion into the culde-sac of the conjunctiva between the sclera of the eyeball and the lid to dispense said drug to the eye over a prolonged period of time, the improvement for rendering the ocular insert more compatible with the eye and the surrounding tissues comprising (1) an inner core comprised of a hydrophobic polymer, said inner core containing the drug and permeable to passage of the drug and (2) a soft flexible 2. The ocular insert of claim 1 wherein said inner core is porous to permit passage of gases and liquids therethrough.

3. The ocular insert of claim 1 wherein said inner core is a matrix ofa hydrophobic polymer permeable to passage of the drug, to meter the passage of drug from the inner core to and through the hydrophilic outer layer.

4. The ocular insert of claim 3 wherein said hydrophilic outer layer is a hydrophilic hydrogel.

5. The ocular insert of claim 3 wherein said hydrophilic outer layer is a hydrophilic hydrogel of a polymer of an ester of acrylic acid or methacrylic acid.

6. The ocular insert of claim 1 wherein said inner core is comprised of a plurality of drug-containing particles.

7. The ocular insert of claim 1 wherein said inner core is a capsule of a hydrophobic polymer, having the drug in the interior chamber thereof, the walls of said capsule being permeable to passage of the drug, to meter the flow of drug from said interior chamber to and through the hydrophilic outer layer.

8. The ocular insert of claim 7 wherein said hydrophilic outer layer is a hydrophilic hydrogel. I

9. The ocular insert of claim 7 wherein said hydrophilic outer layer is a hydrophilic hydrogel of a polymer of an ester of acrylic or methacrylic acid.

10. The ocular insert of claim 1 wherein said hydrophilic outer layer is comprised of a polymer selected from the group consisting of hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross linked hydrophilic polyether gel, cross linked polyvinyl alcohol, cross-linked partially hydrolyzed polyvinyl acetate and cellulosic gel.

11. The ocular insert of claim 1 wherein said drug is an ophthalmic drug.

12. The ocular insert of claim 1 wherein said drug is a systematically active drug which will pass through the eye to the bloodstream and produce a pharmacologic response at a site remote from the eye.

13. The ocular insert of 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 eye.

14. The ocular insert of claim 1 wherein from I microgram to l milligram of drug is incorporated in said tablet.

15. The ocular insert of claim 1 wherein same ranges from 4 to 20 millimeters in length, l to 12 millimeters in width, and 0.1 to l millimeter in thickness.

16. In a drug dispensing ocular insert comprising a flexible body containing a drug and adapted for insertion into the cul de-sac of the conjunctiva between the sclera of the eyeball and the lid to dispense said drug to the eye over a prolonged period of time, the improvement for rendering the ocular insert more compatible with the eye and the surrounding tissues comprising 1) an inner core containing the drug and having an affinity therefor, and said inner core being comprised of material permeable to passage of the drug, which material is independently selected to provide the desired drug release rate, and (l a soft flexible hydrophilic outer layer insoluble in tear liquid, said outer layer also being permeable to passage of the drug and being independently selected for its eye and tissue compatibility, but providing no significant barrier to flow or passage of the drug from the said inner core l to the eye and surrounding tissue, whereby there is no compromise in selection of material for the inner core (1) having the desired release rate for the drug therein by reason of the soft and flexible eye and surrounding tissue compatible outer layer (2 17. The ocular insert of claim 16 wherein said inner core is comprised of a polymer selected from the group consisting of plasticized or unplasticized polyvinyl chloride, plasticized nylon, unplasticized soft nylon, silicone rubber, polyethylene, hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross linked hydrophilic polyether gel, cross linked polyvinyl alcohol, cross linked partially hydrolyzed polyvinyl acetate, cellulosic gel, ion-exchange resin and plasticized polyethylene terephthalate.

18. The ocular insert of claim 17 wherein the drug is chloramphenicol and the polymeric material of the inner core is polyethylene terephthalate.

member selected from the group consisting of pilocarpine and pilocarpine perfluorobutyrate and the polymeric material of the inner core is polyvinyl chloride.

22. The ocular insert of claim 17 wherein the drug is dexamethasone and the polymeric material of the inner core is nylon-66.

I? 1 i t i UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,630,200 Dated December 28, 197]- Inventor(s) Takeru Higuchi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 5, lines 18 through 22 inclusive should be deleted.

Claim 1, line 73, after "flexible" add: hydrophilic outer layer insoluble in tear liquid, compatible with the eye and surrounding tissue and permeable to passage of the drug.

Claim 12, lines 31 and 32, "systematically" should read systemically Claim 16, line 55, "(1)" should read (2) Signed and sealed this 26th day of September 1972.

(SEAL) Attest:

EDWARD MGFLETCHERJR. ROBERT GOT'I'SCHALK Attasting Officer Commissioner of Patents FORM PO'WSO (059) USCOMM DC 60376 P69 v I a [1.5. GOVERNMENT PRINYING OFFICE: 1969 365'334

Claims (22)

1. In a drug dispensing ocular insert comprising a flexible body containing a drug and adapted for insertion into the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid to dispense said drug to the eye over a prolonged period of time, the improvement for rendering the ocular insert more compatible with the eye and the surrounding tissues comprising (1) an inner core comprised of a hydrophobic polymer, said inner core containing the drug and permeable to passage of the drug and (2) a soft flexible hydrophilic outer layer insoluble in tear liquid, compatible with the eye and surrounding tissue and permeable to passage of the drug.

2. The ocular insert of claim 1 wherein said inner core is porous to permit passage of gases and liquids therethrough.

3. The ocular insert of claim 1 wherein said inner core is a matrix of a hydrophobic polymer permeable to passage of the drug, to meter the passage of drug from the inner core to and through the hydrophilic outer layer.

4. The ocular insert of claim 3 wherein said hydrophilic outer layer is a hydrophilic hydrogel.

5. The ocular insert of claim 3 wherein said hydrophilic outer layer is a hydrophilic hydrogel of a polymer of an ester of acrylic acid or methacrylic acid.

6. The ocular insert of claim 1 wherein said inner core is comprised of a plurality of drug-containing particles.

7. The ocular insert of claim 1 wherein said inner core is a capsule of a hydrophobic polymer, having the drug in the interior chamber thereof, the walls of said capsule being permeable to passage of the drug, to meter the flow of drug from said interior chamber to and through the hydrophilic outer layer.

8. The ocular insert of claim 7 wherein said hydrophilic outer layer is a hydrophilic hydrogel.

9. The ocular insert of claim 7 wherein said hydrophilic outer layer is a hydrophilic hydrogel of a polymer of an ester of acrylic or methacrylic acid.

10. The ocular insert of claim 1 wherein said hydrophilic outer layer is comprised of a polymer selected from the group consisting of hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross linked hydrophilic polyether gel, cross linked polyvinyl alcohol, cross linked partially hydrolyzed polyvinyl acetate and cellulosic gel.

11. The ocular insert of claim 1 wherein said drug is an ophthalmic drug.

12. The ocular insert of claim 1 wherein said drug is a systematically active drug which will pass through the eye to the bloodstream and produce a pharmacologic response at a site remote from the eye.

13. The ocUlar insert of 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 eye.

14. The ocular insert of claim 1 wherein from 1 microgram to 1 milligram of drug is incorporated in said tablet.

15. The ocular insert of claim 1 wherein same ranges from 4 to 20 millimeters in length, 1 to 12 millimeters in width, and 0.1 to 1 millimeter in thickness.

16. In a drug dispensing ocular insert comprising a flexible body containing a drug and adapted for insertion into the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid to dispense said drug to the eye over a prolonged period of time, the improvement for rendering the ocular insert more compatible with the eye and the surrounding tissues comprising (1) an inner core containing the drug and having an affinity therefor, and said inner core being comprised of material permeable to passage of the drug, which material is independently selected to provide the desired drug release rate, and (2) a soft flexible hydrophilic outer layer insoluble in tear liquid, said outer layer also being permeable to passage of the drug and being independently selected for its eye and tissue compatibility, but providing no significant barrier to flow or passage of the drug from the said inner core (1) to the eye and surrounding tissue, whereby there is no compromise in selection of material for the inner core (1) having the desired release rate for the drug therein by reason of the soft and flexible, eye and surrounding tissue compatible outer layer (2).

17. The ocular insert of claim 16 wherein said inner core is comprised of a polymer selected from the group consisting of plasticized or unplasticized polyvinyl chloride, plasticized nylon, unplasticized soft nylon, silicone rubber, polyethylene, hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross linked hydrophilic polyether gel, cross linked polyvinyl alcohol, cross linked partially hydrolyzed polyvinyl acetate, cellulosic gel, ion-exchange resin and plasticized polyethylene terephthalate.

18. The ocular insert of claim 17 wherein the drug is chloramphenicol and the polymeric material of the inner core is polyethylene terephthalate.

19. The ocular insert of claim 17 wherein the drug is promethazine trichloroacetate and the polymeric material of the inner core is polyvinyl chloride.

20. The ocular insert of claim 17 wherein the drug is chloramphenicol and the polymeric material of the inner core is polydimethylsiloxane rubber.

21. The ocular insert of claim 17 wherein the drug is a member selected from the group consisting of pilocarpine and pilocarpine perfluorobutyrate and the polymeric material of the inner core is polyvinyl chloride.

22. The ocular insert of claim 17 wherein the drug is dexamethasone and the polymeric material of the inner core is nylon-66.

US831481A 1969-06-09 1969-06-09 Ocular insert Expired - Lifetime US3630200A (en) Applications Claiming Priority (1) Application Number Priority Date Filing Date Title US83148169A 1969-06-09 1969-06-09 Publications (1) Publication Number Publication Date US3630200A true US3630200A (en) 1971-12-28 Family ID=25259154 Family Applications (1) Application Number Title Priority Date Filing Date US831481A Expired - Lifetime US3630200A (en) 1969-06-09 1969-06-09 Ocular insert Country Status (1) Cited By (178) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US3677233A (en) * 1971-03-19 1972-07-18 Pierce H White Jr Livestock insecticide applicator US3797485A (en) * 1971-03-26 1974-03-19 Alza Corp Novel drug delivery device for administering drug into blood circulation in blood vessel US3811444A (en) * 1972-12-27 1974-05-21 Alza Corp Bioerodible ocular device US3826258A (en) * 1972-02-07 1974-07-30 S Abraham Gradual release medicine carrier US3828777A (en) * 1971-11-08 1974-08-13 Alza Corp Microporous ocular device US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent US3854480A (en) * 1969-04-01 1974-12-17 Alza Corp Drug-delivery system US3868445A (en) * 1972-11-30 1975-02-25 Pharmacia Ab Dosage unit containing a substance showing a topical effect on the eye, and a method of preparing same US3901232A (en) * 1973-10-26 1975-08-26 Alza Corp Integrated device for administering beneficial drug at programmed rate US3901969A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of methantheline US3914402A (en) * 1973-06-14 1975-10-21 Alza Corp Ophthalmic dosage form, for releasing medication over time US3960150A (en) * 1971-09-09 1976-06-01 Alza Corporation Bioerodible ocular device US3961628A (en) * 1974-04-10 1976-06-08 Alza Corporation Ocular drug dispensing system FR2290891A1 (en) * 1974-11-14 1976-06-11 Alza Corp SUPPORT INTENDED TO SLOWLY RELEASE AN ACTIVE BODY, IN PARTICULAR A MEDICINAL PRODUCT, AND ITS MANUFACTURE US3963025A (en) * 1974-09-16 1976-06-15 Alza Corporation Ocular drug delivery device US3976071A (en) * 1974-01-07 1976-08-24 Dynatech Corporation Methods of improving control of release rates and products useful in same US3981303A (en) * 1971-09-09 1976-09-21 Alza Corporation Bioerodible ocular device US3986510A (en) * 1971-09-09 1976-10-19 Alza Corporation Bioerodible ocular device US3993073A (en) * 1969-04-01 1976-11-23 Alza Corporation Novel drug delivery device US3993071A (en) * 1971-09-09 1976-11-23 Alza Corporation Bioerodible ocular device US4008719A (en) * 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent US4014334A (en) * 1976-02-02 1977-03-29 Alza Corporation Laminated osmotic system for dispensing beneficial agent US4135514A (en) * 1974-12-23 1979-01-23 Alza Corporation Osmotic releasing system for administering ophthalmic drug to eye of animal US4290426A (en) * 1978-05-04 1981-09-22 Alza Corporation Dispenser for dispensing beneficial agent US4454148A (en) * 1982-09-02 1984-06-12 Merck & Co., Inc. 5-Hydroxy-2-benzothiazolesulfonamide for the topical treatment of elevated intraocular pressure WO1984004680A1 (en) * 1983-05-25 1984-12-06 Alcon Lab Inc Ophthalmic gel WO1984004681A1 (en) * 1983-05-25 1984-12-06 Alcon Lab Inc Ophthalmic solution EP0206741A2 (en) 1985-06-18 1986-12-30 Merck Frosst Canada Inc. Leukotriene antagonists US4659584A (en) * 1985-04-13 1987-04-21 Dr. Karl Thomae Gmbh Eye rod, process and apparatus for loading the same with solutions or suspensions of active substance US4667032A (en) * 1983-01-21 1987-05-19 Merck Frosst Canada, Inc. Phenothiazone derivatives and analogs EP0239306A2 (en) 1986-03-27 1987-09-30 Merck Frosst Canada Inc. Tetrahydrocarbazole esters US4859667A (en) * 1983-01-21 1989-08-22 Merck Frosst Canada, Inc. Pharmaceutical compositions of phenothiazone derivatives and analogs EP0435525A3 (en) * 1989-12-27 1991-12-04 Minnesota Mining And Manufacturing Company Multifocal diffractive ophthalmic lens and method of manufacture US5104899A (en) * 1990-08-13 1992-04-14 Sepracor, Inc. Methods and compositions for treating depression using optically pure fluoxetine EP0480716A1 (en) 1990-10-12 1992-04-15 Merck Frosst Canada Inc. Saturated hydroxyalkylquinoline acids as leukotriene antagonists US5135592A (en) * 1989-12-27 1992-08-04 Minnesota Mining And Manufacturing Company Ultrasonically welded hydrogel ophthalmic lens US5225196A (en) * 1983-11-14 1993-07-06 Columbia Laboratories, Inc. Bioadhesive compositions and methods of treatment therewith WO1993021901A1 (en) * 1992-05-05 1993-11-11 Aiache Jean Marc Galenic form for ocular administration and process for the preparation of same US5314419A (en) * 1992-10-30 1994-05-24 Pelling George E Method for dispensing ophthalmic drugs to the eye EP0577646A4 (en) * 1991-02-21 1994-06-01 Univ Kentucky Res Found Sustained release drug delivery devices US5410054A (en) * 1993-07-20 1995-04-25 Merck Frosst Canada, Inc. Heteroaryl quinolines as inhibitors of leukotriene biosynthesis US5472436A (en) * 1994-07-26 1995-12-05 Fremstad; Daria A. Ocular appliance for delivering medication US5589511A (en) * 1990-08-13 1996-12-31 Sepracor Inc. Method for treating migraine headaches using optically pure S(+) fluoxetine US5618274A (en) * 1994-04-08 1997-04-08 Rosenthal; Kenneth J. Method and device for deep pressurized topical, fornix applied "nerve block" anesthesia US5648396A (en) * 1991-02-04 1997-07-15 Sepracor Inc. Methods for treating depression and other disorders using optically pure R (-) fluoxetine and monoamine oxidase inhibitor US5660851A (en) * 1989-12-26 1997-08-26 Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem Ocular inserts US5902598A (en) * 1997-08-28 1999-05-11 Control Delivery Systems, Inc. Sustained release drug delivery devices US6110973A (en) * 1998-01-29 2000-08-29 Sepracor Methods for treating obesity and weight gain using optically pure (-)-bupropion US6197788B1 (en) 1997-11-26 2001-03-06 Vernalis Research Limited (−)-mefloquine to block puringergic receptors and to treat movement or neurodegenerative disorders US6196993B1 (en) 1998-04-20 2001-03-06 Eyelab Group, Llc Ophthalmic insert and method for sustained release of medication to the eye US6200257B1 (en) * 1999-03-24 2001-03-13 Proxima Therapeutics, Inc. Catheter with permeable hydrogel membrane US6337328B1 (en) 1999-03-01 2002-01-08 Sepracor, Inc. Bupropion metabolites and methods of use US6342496B1 (en) 1999-03-01 2002-01-29 Sepracor Inc. Bupropion metabolites and methods of use US6375972B1 (en) 2000-04-26 2002-04-23 Control Delivery Systems, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof US20020090394A1 (en) * 1995-07-20 2002-07-11 Smithkline Beecham Plc Paroxetine controlled release compositions US6458374B1 (en) 1998-01-29 2002-10-01 Sepracor, Inc. Methods and compositions for treating chronic disorders using optically pure (+)-bupropion US20030021828A1 (en) * 1999-03-22 2003-01-30 Control Delivery Systems Method for treating and/or preventing retinal diseases with substained release corticosteroids US20030064988A1 (en) * 1998-01-21 2003-04-03 Morgan Phillip Frederick Pharmaceutically active morpholinol US6559188B1 (en) 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes US20030096019A1 (en) * 2001-07-02 2003-05-22 Currie Mark G. Methods of using norfluoxetine US20030119168A1 (en) * 2000-02-03 2003-06-26 Corvas International, Inc. Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon US20030134794A1 (en) * 2001-11-20 2003-07-17 Madison Edwin L. Nucleic acid molecules encoding serine protease 17, the encoded polypeptides and methods based thereon US20030162816A1 (en) * 1999-09-17 2003-08-28 Gatlin Marjorie Regan Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes US20030167524A1 (en) * 2000-12-19 2003-09-04 Rooijen Gijs Van Methods for the production of multimeric protein complexes, and related compositions WO2003077847A2 (en) 2002-03-12 2003-09-25 Merck & Co., Inc. Substituted amides US6664397B1 (en) 1997-03-07 2003-12-16 Vernalis Research Limited Use of (+)mefloquine for the treatment of malaria US20040009222A1 (en) * 2002-05-07 2004-01-15 Control Delivery Systems, Inc. Processes for forming a drug delivery device US6734213B2 (en) 1999-01-20 2004-05-11 Smithkline Beecham Corporation Pharmaceutically active morpholinol WO2004081001A1 (en) 2003-02-13 2004-09-23 Banyu Pharmaceutical Co., Ltd. Novel 2-pyridinecarboxamide derivatives US20040208910A1 (en) * 2000-04-26 2004-10-21 Control Delivery Systems, Inc. Sustained release device and method for ocular delivery of adrenergic agents US20050026882A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease US6855820B2 (en) 1999-01-20 2005-02-15 Smithkline Beecham Corporation Pharmaceutically active morpholinol WO2005066126A1 (en) 2003-12-23 2005-07-21 Eli Lilly And Company Cb1 modulator compounds US20050209295A1 (en) * 2004-03-16 2005-09-22 Kohn Leonard D Methimazole derivatives and tautomeric cyclic thiones to inhibit cell adhesion WO2005089767A1 (en) 2004-03-12 2005-09-29 Barton Aron Kamen Use of aminopterin for treating cancer and inflammatory disorders US6951873B1 (en) 1999-04-27 2005-10-04 Pfizer Inc. Methods for treating age-related behavioral disorders in companion animals WO2005051234A3 (en) * 2003-11-13 2005-11-10 Control Delivery Sys Inc Injectable sustained release implant having a bioerodible matrix core and a bioerodible skin US6998400B2 (en) 1998-01-22 2006-02-14 Smithkline Beecham Corporation Pharmaceutically active morpholinol US20060058365A1 (en) * 2004-08-06 2006-03-16 Kohn Leonard D Compositions and methods for treatment of colitis WO2006049304A1 (en) 2004-11-02 2006-05-11 Banyu Pharmaceutical Co., Ltd Aryloxy-substituted benzimidazole derivatives US20060134176A1 (en) * 2004-12-22 2006-06-22 Bausch & Lomb Incorporated Pharmaceutical delivery system and method of use US20060185678A1 (en) * 2005-02-03 2006-08-24 Bronnenkant Lance J Devices for delivering agents to a vaginal tract WO2006091871A1 (en) 2005-02-23 2006-08-31 Halozyme Therapeutics, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US20060194840A1 (en) * 2003-09-19 2006-08-31 David Gozal Method for treating snoring and sleep apnea with leukotriene antagonists US7105333B2 (en) 2001-03-27 2006-09-12 Deadreon Corporation Nucleic acid molecules encoding a transmembrane serine protease 9, the encoded polypeptides and methods based thereon US20060211752A1 (en) * 2004-03-16 2006-09-21 Kohn Leonard D Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression US7112430B2 (en) 2001-05-14 2006-09-26 Dendreon Corporation Nucleic acid molecules encoding a transmembrane serine protease 10, the encoded polypeptides and methods based thereon US7125703B2 (en) 2001-03-13 2006-10-24 Dendreon Corporation Nucleic acid molecules encoding a transmembrane serine protease 7, the encoded polypeptides and methods based thereon US20060286102A1 (en) * 2004-05-14 2006-12-21 Pei Jin Cell surface receptor isoforms and methods of identifying and using the same US7172892B2 (en) 2001-03-22 2007-02-06 Dendreon Corporation Nucleic acid molecules encoding serine protease CVSP14, the encoded polypeptides and methods based thereon WO2007037534A1 (en) 2005-09-30 2007-04-05 Banyu Pharmaceutical Co., Ltd. 2-heteroaryl-substituted indole derivative US20070087406A1 (en) * 2005-05-04 2007-04-19 Pei Jin Isoforms of receptor for advanced glycation end products (RAGE) and methods of identifying and using same US20070161081A1 (en) * 2005-11-10 2007-07-12 Receptor Biologix, Inc. Hepatocyte growth factor intron fusion proteins US7276364B1 (en) 1999-11-18 2007-10-02 Dendreon Corporation Nucleic acids encoding endotheliases, endotheliases and uses thereof US20070293190A1 (en) * 2006-06-14 2007-12-20 Yuya Ota Remote control system and remote control method WO2008044777A1 (en) 2006-10-06 2008-04-17 Banyu Pharmaceutical Co., Ltd. 2-pyridinecarboxamide derivative having gk-activating activity WO2008066131A1 (en) 2006-12-01 2008-06-05 Banyu Pharmaceutical Co., Ltd. Novel phenyl-isoxazol-3-ol derivative WO2008094476A1 (en) 2007-01-31 2008-08-07 Merck & Co., Inc. Substituted pyrano [2, 3 - b] pyridine derivatives as cannabinoid -1 receptor modulators EP2011507A2 (en) 1999-09-17 2009-01-07 Novartis AG Pharmaceutical composition of nateglinide and another antidiabetic agent WO2009063821A1 (en) 2007-11-12 2009-05-22 Banyu Pharmaceutical Co., Ltd. Heteroaryloxy quinazoline derivative WO2009081782A1 (en) 2007-12-25 2009-07-02 Banyu Pharmaceutical Co., Ltd. N-pyrazole-2-pyridinecarboxamide derivative US7585517B2 (en) * 2003-09-18 2009-09-08 Macusight, Inc. Transscleral delivery WO2009147990A1 (en) 2008-06-02 2009-12-10 萬有製薬株式会社 Novel isoxazole derivative US20090317476A1 (en) * 2003-07-31 2009-12-24 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease US20100004304A1 (en) * 2004-03-16 2010-01-07 Kohn Leonard D Methods and compositions for the treatment of malignant melanoma, breast, prostate, colon, papillary thyroid and pancreatic cancer US20100015698A1 (en) * 2002-12-16 2010-01-21 Halozyme, Inc. Human Chondroitinase Glycoprotein (CHASEGP), Process for Preparing the Same, and Pharmaceutical Compositions Comprising Thereof US20100055093A1 (en) * 2006-06-12 2010-03-04 Receptor Biologix Inc. Pan-cell surface receptor-specific therapeutics EP2163643A1 (en) 2003-03-05 2010-03-17 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents WO2010077297A1 (en) 2008-12-09 2010-07-08 Halozyme, Inc. Extended soluble ph20 polypeptides and uses thereof US20100196423A1 (en) * 2005-02-23 2010-08-05 Bookbinder Louis H Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases WO2010095767A1 (en) 2009-02-23 2010-08-26 Banyu Pharmaceutical Co.,Ltd. Pyrimidin-4(3h)-one derivatives US20100222394A1 (en) * 2007-09-28 2010-09-02 Kenichi Asakawa Method for producing pyrazol-3-yl-benzamide derivative WO2010102262A1 (en) 2009-03-06 2010-09-10 Halozyme, Inc. Temperature sensitive mutants of matrix metalloprotease 1 und uses thereof WO2010104195A1 (en) 2009-03-11 2010-09-16 Banyu Pharmaceutical Co.,Ltd. Novel isoindolin-1-one derivative US20100278801A1 (en) * 2007-10-16 2010-11-04 Shepard H Michael Compositions comprising optimized her1 and her3 multimers and methods of use thereof WO2010127452A1 (en) 2009-05-04 2010-11-11 The Royal Institution For The Advancement Of Learning/Mcgill University 5-oxo-ete receptor antagonist compounds US20110009463A1 (en) * 2007-10-17 2011-01-13 Yuri Karl Petersson Geranylgeranyl transferase inhibitors and methods of making and using the same US20110195978A1 (en) * 2008-10-10 2011-08-11 Purdue Research Foundation Compounds for treatment of alzheimer's disease WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents US20110230505A1 (en) * 2008-11-20 2011-09-22 Purdue Research Foundation Quinazoline inhibitors of bace 1 and methods of using EP2402437A2 (en) 2006-07-05 2012-01-04 Catalyst Biosciences, Inc. Protease screening methods and proteases identified thereby US8222271B2 (en) 2006-03-23 2012-07-17 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents US8367097B2 (en) 2005-02-09 2013-02-05 Santen Pharmaceutical Co., Ltd. Liquid formulations for treatment of diseases or conditions US20130062809A1 (en) * 2011-09-13 2013-03-14 Vista Scientific Llc Sustained Release Ocular Drug Delivery Devices and Methods of Manufacture WO2013040501A1 (en) 2011-09-16 2013-03-21 Pharmathene, Inc. Compositions and combinations of organophosphorus bioscavengers and hyaluronan-degrading enzymes, and uses thereof WO2013101926A1 (en) 2011-12-28 2013-07-04 Allergan, Inc. Benzimidazole derivatives as selective blockers of persistent sodium current US8492400B2 (en) 2006-02-09 2013-07-23 Santen Pharmaceutical Co., Ltd. Stable formulations, and methods of their preparation and use WO2013142380A1 (en) 2012-03-22 2013-09-26 The Regents Of The University Of California Oncovector nucleic acid molecules and methods of use WO2013151774A1 (en) 2012-04-04 2013-10-10 Halozyme, Inc. Combination therapy with an anti - hyaluronan agent and a tumor - targeted taxane EP2662090A1 (en) 2008-04-14 2013-11-13 Halozyme, Inc. Modified hyaluronidases and uses in treating hyaluronan-associated diseases and conditions WO2014031465A1 (en) 2012-08-22 2014-02-27 Merck Sharp & Dohme Corp. Novel azabenzimidazole tetrahydropyran derivatives US8663639B2 (en) 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions WO2014062856A1 (en) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods WO2014093189A1 (en) 2012-12-10 2014-06-19 Merck Sharp & Dohme Corp. Methods of treating diabetes by administering a glucagon receptor antagonist in combination with a cholesterol absorption inhibitor WO2014096852A1 (en) 2012-12-21 2014-06-26 Coopervision International Holding Company, Lp Antimicrobial ophthalmic contact lenses WO2014096853A1 (en) 2012-12-21 2014-06-26 Coopervision International Holding Company, Lp Methods of Manufacturing Contact Lenses For Delivery of Beneficial Agents WO2014096854A2 (en) 2012-12-21 2014-06-26 Coopervision International Holding Company, Lp Ophthalmic devices for delivery of beneficial agents US8765166B2 (en) 2010-05-17 2014-07-01 Novaer Holdings, Inc. Drug delivery devices for delivery of ocular therapeutic agents WO2014107745A1 (en) 2013-01-07 2014-07-10 Halozyme, Inc. Metal sensitive mutants of matrix metalloproteases and uses thereof EP2772225A1 (en) * 2001-03-15 2014-09-03 THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Ocular therapeutic agent delivery devices and methods for making and using such devices WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents US8859780B2 (en) 2011-12-28 2014-10-14 Allergan, Inc. Benzimidazole derivatives as selective blockers of persistent sodium current US8859590B2 (en) 2008-12-05 2014-10-14 Purdue Research Foundation Inhibitors of BACE1 and methods for treating Alzheimer's disease US8871241B2 (en) 2002-05-07 2014-10-28 Psivida Us, Inc. Injectable sustained release delivery devices EP2717813A4 (en) * 2011-06-06 2014-11-05 Oak Crest Inst Of Science Drug delivery device employing wicking release window WO2015003167A1 (en) 2013-07-03 2015-01-08 Halozyme, Inc. Thermally stable ph20 hyaluronidase variants and uses thereof WO2015009534A2 (en) 2013-07-16 2015-01-22 Allergan, Inc. Hcn inhibitors affecting ganglion cell function and visual function US8969583B2 (en) 2011-12-28 2015-03-03 Allergan, Inc. 3-phenyl-5-ureidoisothiazole-4-carboximide and 3-amino-5-phenylisothiazole derivatives as kinase inhibitors US9034870B2 (en) 2012-07-13 2015-05-19 Purdue Research Foundation Azaindenoisoquinoline topoisomerase I inhibitors US9062057B2 (en) 2010-03-19 2015-06-23 Purdue Research Foundation CCR5 antagonists for treating HIV WO2016033555A1 (en) 2014-08-28 2016-03-03 Halozyme, Inc. Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor US9296747B1 (en) 2014-10-10 2016-03-29 Allergan, Inc. Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2 WO2016061286A2 (en) 2014-10-14 2016-04-21 Halozyme, Inc. Compositions of adenosine deaminase-2 (ada2), variants thereof and methods of using same US9359336B2 (en) 2014-10-09 2016-06-07 Allergan, Inc. Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors US9403803B2 (en) 2014-10-08 2016-08-02 Allergan, Inc. Indole-3-carboxamides as kinase inhibitors US9447401B2 (en) 2011-12-30 2016-09-20 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof WO2016176634A1 (en) 2015-04-30 2016-11-03 The Regents Of The University Of Colorado, A Body Corporate Polycyclic indoline and indolenine compounds US9775889B2 (en) 2008-03-06 2017-10-03 Halozyme, Inc. Methods of treatment of cellulite US9867828B2 (en) 2005-03-11 2018-01-16 Aminopterin Llc Aminopterin dosage forms US10098836B2 (en) 2013-05-02 2018-10-16 Retina Foundation Of The Southwest Method for forming a molded two-layer ocular implant US10172854B2 (en) 2012-02-27 2019-01-08 Biovista, Inc. Compositions and methods for treating mitochondrial diseases WO2019014398A1 (en) 2017-07-11 2019-01-17 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof WO2019222435A1 (en) 2018-05-16 2019-11-21 Halozyme, Inc. Methods of selecting subjects for combination cancer therapy with a polymer-conjugated soluble ph20 WO2020014543A2 (en) 2018-07-11 2020-01-16 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof WO2020047161A2 (en) 2018-08-28 2020-03-05 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof WO2020176809A1 (en) 2019-02-27 2020-09-03 Actym Therapeutics, Inc. Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment WO2021097144A2 (en) 2019-11-12 2021-05-20 Actym Therapeutics, Inc. Immunostimulatory bacteria delivery platforms and their use for delivery of therapeutic products WO2022036159A2 (en) 2020-08-12 2022-02-17 Actym Therapeutics, Inc. Immunostimulatory bacteria-based vaccines, therapeutics, and rna delivery platforms US11389435B2 (en) 2008-09-15 2022-07-19 Biovista, Inc. Compositions and methods for treating epilepsy WO2023168426A1 (en) 2022-03-03 2023-09-07 Enosi Therapeutics Corporation Compositions and cells containing mixtures of oligo-trap fusion proteins (ofps) and uses thereof US20240065970A1 (en) * 2020-11-04 2024-02-29 Aerie Pharmaceuticals, Inc. Medical implant WO2024091863A1 (en) 2022-10-25 2024-05-02 Starrock Pharma Llc Combinatorial, and rotational combinatorial therapies for obesity and other diseases US12024709B2 (en) 2019-02-27 2024-07-02 Actym Therapeutics, Inc. Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment WO2024186690A2 (en) 2023-03-03 2024-09-12 Enosi Therapeutics Corporation Oligo-trap fusion proteins (ofps) and uses thereof US12257184B2 (en) 2019-10-24 2025-03-25 Denis LaBombard Ocular device and drug delivery system, with case Citations (6) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US3006338A (en) * 1953-10-12 1961-10-31 Johnson & Johnson Non-adherent surgical dressing US3220960A (en) * 1960-12-21 1965-11-30 Wichterle Otto Cross-linked hydrophilic polymers and articles made therefrom US3301257A (en) * 1963-07-15 1967-01-31 Johnson & Johnson Absorbent surgical dressing US3416530A (en) * 1966-03-02 1968-12-17 Richard A. Ness Eyeball medication dispensing tablet US3490454A (en) * 1966-10-21 1970-01-20 United Merchants & Mfg Catamenial products having a coating of rupturable microcapsules containing medicants US3520949A (en) * 1966-07-26 1970-07-21 Nat Patent Dev Corp Hydrophilic polymers,articles and methods of making same Patent Citations (6) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US3006338A (en) * 1953-10-12 1961-10-31 Johnson & Johnson Non-adherent surgical dressing US3220960A (en) * 1960-12-21 1965-11-30 Wichterle Otto Cross-linked hydrophilic polymers and articles made therefrom US3301257A (en) * 1963-07-15 1967-01-31 Johnson & Johnson Absorbent surgical dressing US3416530A (en) * 1966-03-02 1968-12-17 Richard A. Ness Eyeball medication dispensing tablet US3520949A (en) * 1966-07-26 1970-07-21 Nat Patent Dev Corp Hydrophilic polymers,articles and methods of making same US3490454A (en) * 1966-10-21 1970-01-20 United Merchants & Mfg Catamenial products having a coating of rupturable microcapsules containing medicants Cited By (316) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US3993073A (en) * 1969-04-01 1976-11-23 Alza Corporation Novel drug delivery device US3854480A (en) * 1969-04-01 1974-12-17 Alza Corp Drug-delivery system US3677233A (en) * 1971-03-19 1972-07-18 Pierce H White Jr Livestock insecticide applicator US3797485A (en) * 1971-03-26 1974-03-19 Alza Corp Novel drug delivery device for administering drug into blood circulation in blood vessel US3960150A (en) * 1971-09-09 1976-06-01 Alza Corporation Bioerodible ocular device US3986510A (en) * 1971-09-09 1976-10-19 Alza Corporation Bioerodible ocular device US3981303A (en) * 1971-09-09 1976-09-21 Alza Corporation Bioerodible ocular device US3993071A (en) * 1971-09-09 1976-11-23 Alza Corporation Bioerodible ocular device US3828777A (en) * 1971-11-08 1974-08-13 Alza Corp Microporous ocular device US3826258A (en) * 1972-02-07 1974-07-30 S Abraham Gradual release medicine carrier US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent US3868445A (en) * 1972-11-30 1975-02-25 Pharmacia Ab Dosage unit containing a substance showing a topical effect on the eye, and a method of preparing same US3811444A (en) * 1972-12-27 1974-05-21 Alza Corp Bioerodible ocular device US3914402A (en) * 1973-06-14 1975-10-21 Alza Corp Ophthalmic dosage form, for releasing medication over time US3901969A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of methantheline US3901232A (en) * 1973-10-26 1975-08-26 Alza Corp Integrated device for administering beneficial drug at programmed rate US3976071A (en) * 1974-01-07 1976-08-24 Dynatech Corporation Methods of improving control of release rates and products useful in same US3961628A (en) * 1974-04-10 1976-06-08 Alza Corporation Ocular drug dispensing system US3963025A (en) * 1974-09-16 1976-06-15 Alza Corporation Ocular drug delivery device FR2290891A1 (en) * 1974-11-14 1976-06-11 Alza Corp SUPPORT INTENDED TO SLOWLY RELEASE AN ACTIVE BODY, IN PARTICULAR A MEDICINAL PRODUCT, AND ITS MANUFACTURE US4135514A (en) * 1974-12-23 1979-01-23 Alza Corporation Osmotic releasing system for administering ophthalmic drug to eye of animal US4142526A (en) * 1974-12-23 1979-03-06 Alza Corporation Osmotic releasing system with means for changing release therefrom US4008719A (en) * 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent US4014334A (en) * 1976-02-02 1977-03-29 Alza Corporation Laminated osmotic system for dispensing beneficial agent US4290426A (en) * 1978-05-04 1981-09-22 Alza Corporation Dispenser for dispensing beneficial agent US4454148A (en) * 1982-09-02 1984-06-12 Merck & Co., Inc. 5-Hydroxy-2-benzothiazolesulfonamide for the topical treatment of elevated intraocular pressure US4667032A (en) * 1983-01-21 1987-05-19 Merck Frosst Canada, Inc. Phenothiazone derivatives and analogs US4859667A (en) * 1983-01-21 1989-08-22 Merck Frosst Canada, Inc. Pharmaceutical compositions of phenothiazone derivatives and analogs WO1984004680A1 (en) * 1983-05-25 1984-12-06 Alcon Lab Inc Ophthalmic gel WO1984004681A1 (en) * 1983-05-25 1984-12-06 Alcon Lab Inc Ophthalmic solution US5225196A (en) * 1983-11-14 1993-07-06 Columbia Laboratories, Inc. Bioadhesive compositions and methods of treatment therewith US4659584A (en) * 1985-04-13 1987-04-21 Dr. Karl Thomae Gmbh Eye rod, process and apparatus for loading the same with solutions or suspensions of active substance EP0206741A2 (en) 1985-06-18 1986-12-30 Merck Frosst Canada Inc. Leukotriene antagonists EP0239306A2 (en) 1986-03-27 1987-09-30 Merck Frosst Canada Inc. Tetrahydrocarbazole esters US5660851A (en) * 1989-12-26 1997-08-26 Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem Ocular inserts US5152788A (en) * 1989-12-27 1992-10-06 Minnesota Mining And Manufacturing Company Multifocal diffractive ophthalmic lens and method of manufacture EP0435525A3 (en) * 1989-12-27 1991-12-04 Minnesota Mining And Manufacturing Company Multifocal diffractive ophthalmic lens and method of manufacture US5135592A (en) * 1989-12-27 1992-08-04 Minnesota Mining And Manufacturing Company Ultrasonically welded hydrogel ophthalmic lens US5589511A (en) * 1990-08-13 1996-12-31 Sepracor Inc. Method for treating migraine headaches using optically pure S(+) fluoxetine US5104899A (en) * 1990-08-13 1992-04-14 Sepracor, Inc. Methods and compositions for treating depression using optically pure fluoxetine EP0480716A1 (en) 1990-10-12 1992-04-15 Merck Frosst Canada Inc. Saturated hydroxyalkylquinoline acids as leukotriene antagonists US5708035A (en) * 1991-02-04 1998-01-13 Sepracor Inc. Methods of use and compositions of R(-) fluoxetine US5648396A (en) * 1991-02-04 1997-07-15 Sepracor Inc. Methods for treating depression and other disorders using optically pure R (-) fluoxetine and monoamine oxidase inhibitor EP0577646A4 (en) * 1991-02-21 1994-06-01 Univ Kentucky Res Found Sustained release drug delivery devices US5378475A (en) * 1991-02-21 1995-01-03 University Of Kentucky Research Foundation Sustained release drug delivery devices EP0861659A1 (en) * 1991-02-21 1998-09-02 University Of Kentucky Research Foundation Sustained release drug delivery devices WO1993021901A1 (en) * 1992-05-05 1993-11-11 Aiache Jean Marc Galenic form for ocular administration and process for the preparation of same FR2690846A1 (en) * 1992-05-05 1993-11-12 Aiache Jean Marc Galenic form for ocular administration and method of preparation US5766619A (en) * 1992-05-05 1998-06-16 Aiache; Jean-Marc Pharmaceutical dosage form for ocular administration and preparation process US5314419A (en) * 1992-10-30 1994-05-24 Pelling George E Method for dispensing ophthalmic drugs to the eye US5410054A (en) * 1993-07-20 1995-04-25 Merck Frosst Canada, Inc. Heteroaryl quinolines as inhibitors of leukotriene biosynthesis US5618274A (en) * 1994-04-08 1997-04-08 Rosenthal; Kenneth J. Method and device for deep pressurized topical, fornix applied "nerve block" anesthesia US5472436A (en) * 1994-07-26 1995-12-05 Fremstad; Daria A. Ocular appliance for delivering medication US20020090394A1 (en) * 1995-07-20 2002-07-11 Smithkline Beecham Plc Paroxetine controlled release compositions US7229640B2 (en) 1995-07-20 2007-06-12 Smithkline Beecham P.L.C. Paroxetine controlled release compositions US6664397B1 (en) 1997-03-07 2003-12-16 Vernalis Research Limited Use of (+)mefloquine for the treatment of malaria US5902598A (en) * 1997-08-28 1999-05-11 Control Delivery Systems, Inc. Sustained release drug delivery devices US6197788B1 (en) 1997-11-26 2001-03-06 Vernalis Research Limited (−)-mefloquine to block puringergic receptors and to treat movement or neurodegenerative disorders US20030064988A1 (en) * 1998-01-21 2003-04-03 Morgan Phillip Frederick Pharmaceutically active morpholinol US20060189612A1 (en) * 1998-01-21 2006-08-24 Smithkline Beecham Corporation Pharmaceutically active morpholinol US7098206B2 (en) 1998-01-21 2006-08-29 Smithkline Beecham Corporation Pharmaceutically active morpholinol US6998400B2 (en) 1998-01-22 2006-02-14 Smithkline Beecham Corporation Pharmaceutically active morpholinol US6369113B2 (en) 1998-01-29 2002-04-09 Sepracor, Inc. Method for treating depression using optically pure (−)-bupropion US6277887B1 (en) 1998-01-29 2001-08-21 Sepracor, Inc. Methods for treating Parkinson's disease using optically pure (−)-bupropion US6451860B1 (en) 1998-01-29 2002-09-17 Sepracor, Inc. Methods for treating depression and other disorders using optically pure (−)-bupropion US6458374B1 (en) 1998-01-29 2002-10-01 Sepracor, Inc. Methods and compositions for treating chronic disorders using optically pure (+)-bupropion US6495605B2 (en) 1998-01-29 2002-12-17 Sepracor Inc. Methods and compositions for aiding in smoking cessation and for treating pain and other disorders using optically pure (+)-bupropion US20030022942A1 (en) * 1998-01-29 2003-01-30 Sepracor, Inc. Methods and compositions for treating depression and other disorders using optically pure (-)-bupropion US6110973A (en) * 1998-01-29 2000-08-29 Sepracor Methods for treating obesity and weight gain using optically pure (-)-bupropion US6196993B1 (en) 1998-04-20 2001-03-06 Eyelab Group, Llc Ophthalmic insert and method for sustained release of medication to the eye US20050096318A1 (en) * 1999-01-20 2005-05-05 Toby Broom Pharmaceutically active morpholinol US6855820B2 (en) 1999-01-20 2005-02-15 Smithkline Beecham Corporation Pharmaceutically active morpholinol US6734213B2 (en) 1999-01-20 2004-05-11 Smithkline Beecham Corporation Pharmaceutically active morpholinol US6337328B1 (en) 1999-03-01 2002-01-08 Sepracor, Inc. Bupropion metabolites and methods of use US20020052340A1 (en) * 1999-03-01 2002-05-02 Jerussi Thomas P. Bupropion metabolites and methods of their synthesis and use US6342496B1 (en) 1999-03-01 2002-01-29 Sepracor Inc. Bupropion metabolites and methods of use US20060058300A1 (en) * 1999-03-01 2006-03-16 Sepracor Inc. Intermediates of bupropion metabolites synthesis US20100125070A1 (en) * 1999-03-01 2010-05-20 Fang Kevin Qun Bupropion Metabolites and Methods of Their Synthesis and Use US8252307B2 (en) 1999-03-22 2012-08-28 Psivida Us, Inc. Method for treating and/or preventing retinal diseases with sustained release corticosteroids US20030021828A1 (en) * 1999-03-22 2003-01-30 Control Delivery Systems Method for treating and/or preventing retinal diseases with substained release corticosteroids US20100168073A1 (en) * 1999-03-22 2010-07-01 Paul Ashton Method for treating and/or preventing retinal diseases with sustained release corticosteroids US6200257B1 (en) * 1999-03-24 2001-03-13 Proxima Therapeutics, Inc. Catheter with permeable hydrogel membrane US6537194B1 (en) 1999-03-24 2003-03-25 Proxima Therapeutics, Inc. Catheter with permeable hydrogel membrane US6951873B1 (en) 1999-04-27 2005-10-04 Pfizer Inc. Methods for treating age-related behavioral disorders in companion animals US6878749B2 (en) 1999-09-17 2005-04-12 Novartis Ag Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes US6559188B1 (en) 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes US20070275928A1 (en) * 1999-09-17 2007-11-29 Gatlin Marjorie R Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes US20050124663A1 (en) * 1999-09-17 2005-06-09 Gatlin Marjorie R. Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes EP2011507A2 (en) 1999-09-17 2009-01-07 Novartis AG Pharmaceutical composition of nateglinide and another antidiabetic agent US20030162816A1 (en) * 1999-09-17 2003-08-28 Gatlin Marjorie Regan Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes US20100076084A1 (en) * 1999-09-17 2010-03-25 Marjorie Regan Gatlin Method of Treating Metabolic Disorders, Especially Diabetes, or a Disease or Condition Associated with Diabetes US7276364B1 (en) 1999-11-18 2007-10-02 Dendreon Corporation Nucleic acids encoding endotheliases, endotheliases and uses thereof US7700341B2 (en) 2000-02-03 2010-04-20 Dendreon Corporation Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon US20110105731A1 (en) * 2000-02-03 2011-05-05 Madison Edwin L Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon US7888092B2 (en) 2000-02-03 2011-02-15 Dendreon Corporation Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon US20030119168A1 (en) * 2000-02-03 2003-06-26 Corvas International, Inc. Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon US8574613B2 (en) 2000-04-26 2013-11-05 Psivida Us, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof US9849085B2 (en) 2000-04-26 2017-12-26 Psivida Us Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof US8574659B2 (en) 2000-04-26 2013-11-05 Psivida Us, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof US20040208910A1 (en) * 2000-04-26 2004-10-21 Control Delivery Systems, Inc. Sustained release device and method for ocular delivery of adrenergic agents US9192579B2 (en) 2000-04-26 2015-11-24 Psivida Us, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof US6375972B1 (en) 2000-04-26 2002-04-23 Control Delivery Systems, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof US20030167524A1 (en) * 2000-12-19 2003-09-04 Rooijen Gijs Van Methods for the production of multimeric protein complexes, and related compositions US7125703B2 (en) 2001-03-13 2006-10-24 Dendreon Corporation Nucleic acid molecules encoding a transmembrane serine protease 7, the encoded polypeptides and methods based thereon EP2772225A1 (en) * 2001-03-15 2014-09-03 THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Ocular therapeutic agent delivery devices and methods for making and using such devices US7172892B2 (en) 2001-03-22 2007-02-06 Dendreon Corporation Nucleic acid molecules encoding serine protease CVSP14, the encoded polypeptides and methods based thereon US7105333B2 (en) 2001-03-27 2006-09-12 Deadreon Corporation Nucleic acid molecules encoding a transmembrane serine protease 9, the encoded polypeptides and methods based thereon US7112430B2 (en) 2001-05-14 2006-09-26 Dendreon Corporation Nucleic acid molecules encoding a transmembrane serine protease 10, the encoded polypeptides and methods based thereon US7034059B2 (en) 2001-07-02 2006-04-25 Sepracor Inc. Methods of using norfluoxetine US20030096019A1 (en) * 2001-07-02 2003-05-22 Currie Mark G. Methods of using norfluoxetine US20030134794A1 (en) * 2001-11-20 2003-07-17 Madison Edwin L. Nucleic acid molecules encoding serine protease 17, the encoded polypeptides and methods based thereon WO2003077847A2 (en) 2002-03-12 2003-09-25 Merck & Co., Inc. Substituted amides US8871241B2 (en) 2002-05-07 2014-10-28 Psivida Us, Inc. Injectable sustained release delivery devices US20040009222A1 (en) * 2002-05-07 2004-01-15 Control Delivery Systems, Inc. Processes for forming a drug delivery device EP2218779A1 (en) 2002-12-16 2010-08-18 Halozyme, Inc. Human chondroitinase glycoprotein (chasegp), process for preparing the same, and pharmaceutical compositions comprising thereof EP2298874A1 (en) 2002-12-16 2011-03-23 Halozyme, Inc. Human chondroitinase glycoprotein (CHASEGP), process for preparing the same, and pharmaceutical compositions comprising thereof US8815558B2 (en) 2002-12-16 2014-08-26 Halozyme, Inc. Human chondroitinase glycoprotein (CHASEGP), process for preparing the same, and pharmaceutical compositions comprising thereof US20100015698A1 (en) * 2002-12-16 2010-01-21 Halozyme, Inc. Human Chondroitinase Glycoprotein (CHASEGP), Process for Preparing the Same, and Pharmaceutical Compositions Comprising Thereof WO2004081001A1 (en) 2003-02-13 2004-09-23 Banyu Pharmaceutical Co., Ltd. Novel 2-pyridinecarboxamide derivatives EP2311973A1 (en) 2003-03-05 2011-04-20 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US8765685B2 (en) 2003-03-05 2014-07-01 Halozyme, Inc. Methods for treating edema by administering a Soluble Hyaluronidase Glycoprotein (sHASEGP) US8772246B2 (en) 2003-03-05 2014-07-08 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof EP3009517A1 (en) 2003-03-05 2016-04-20 Halozyme, Inc. Soluble hyaluronidase glycoprotein (shasegp), process for preparing the same, uses and pharmaceutical compositions comprising thereof US8450470B2 (en) 2003-03-05 2013-05-28 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US20110008309A1 (en) * 2003-03-05 2011-01-13 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US11723959B2 (en) 2003-03-05 2023-08-15 Halozyme, Inc. Preparation of mammalian oocyte for fertilization via a soluble human PH20 hyaluronidase polypeptide US7871607B2 (en) 2003-03-05 2011-01-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US8431124B2 (en) 2003-03-05 2013-04-30 Halozyme, Inc. Methods for treating a disease characterized by an excess of hyaluronan by administering a soluble hyaluronidase glycoprotein (sHASEGP) US8431380B2 (en) 2003-03-05 2013-04-30 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US9562223B2 (en) 2003-03-05 2017-02-07 Halozyme, Inc. Methods for reducing intraocular pressure by administering a soluble hyaluronidase glycoprotein (sHASEGP) EP2163643A1 (en) 2003-03-05 2010-03-17 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US8202517B2 (en) 2003-03-05 2012-06-19 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US8105586B2 (en) 2003-03-05 2012-01-31 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases EP2177620A1 (en) 2003-03-05 2010-04-21 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof EP2405015A2 (en) 2003-03-05 2012-01-11 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US10898551B2 (en) 2003-03-05 2021-01-26 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US9677061B2 (en) 2003-03-05 2017-06-13 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US9677062B2 (en) 2003-03-05 2017-06-13 Halozyme, Inc. Hyaluronidase and factor VIII compositions US10286044B2 (en) 2003-03-05 2019-05-14 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US7767429B2 (en) 2003-03-05 2010-08-03 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof EP2330213A1 (en) 2003-03-05 2011-06-08 Halozyme, Inc. Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof US20090317476A1 (en) * 2003-07-31 2009-12-24 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease US20050026882A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease US7585517B2 (en) * 2003-09-18 2009-09-08 Macusight, Inc. Transscleral delivery US20110166114A1 (en) * 2003-09-19 2011-07-07 University Of Louisville Research Foundation Method for treating snoring and sleep apnea with leukotriene antagonists US20060194840A1 (en) * 2003-09-19 2006-08-31 David Gozal Method for treating snoring and sleep apnea with leukotriene antagonists EP2233112A3 (en) * 2003-11-13 2011-03-02 PSivida US Inc. Injectable sustained release implant having a bioerodible matrix core and a bioerodible skin AU2004292957B2 (en) * 2003-11-13 2010-09-09 Eyepoint Pharmaceuticals Us, Inc. Injectable sustained release implant having a bioerodible matrix core and a bioerodible skin WO2005051234A3 (en) * 2003-11-13 2005-11-10 Control Delivery Sys Inc Injectable sustained release implant having a bioerodible matrix core and a bioerodible skin AU2004292957C1 (en) * 2003-11-13 2011-04-28 Eyepoint Pharmaceuticals Us, Inc. Injectable sustained release implant having a bioerodible matrix core and a bioerodible skin WO2005066126A1 (en) 2003-12-23 2005-07-21 Eli Lilly And Company Cb1 modulator compounds US9211315B2 (en) 2004-03-05 2015-12-15 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US8580252B2 (en) 2004-03-05 2013-11-12 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US8257699B2 (en) 2004-03-05 2012-09-04 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US10016491B2 (en) 2004-03-05 2018-07-10 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases WO2005089767A1 (en) 2004-03-12 2005-09-29 Barton Aron Kamen Use of aminopterin for treating cancer and inflammatory disorders US20050209295A1 (en) * 2004-03-16 2005-09-22 Kohn Leonard D Methimazole derivatives and tautomeric cyclic thiones to inhibit cell adhesion US20060211752A1 (en) * 2004-03-16 2006-09-21 Kohn Leonard D Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression US9326972B2 (en) 2004-03-16 2016-05-03 Ohio University Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression US20100004304A1 (en) * 2004-03-16 2010-01-07 Kohn Leonard D Methods and compositions for the treatment of malignant melanoma, breast, prostate, colon, papillary thyroid and pancreatic cancer US20060286102A1 (en) * 2004-05-14 2006-12-21 Pei Jin Cell surface receptor isoforms and methods of identifying and using the same US7928132B2 (en) 2004-08-06 2011-04-19 Ohio University Methods for the amelioration of episodes of acute or chronic ulcerative colitis US20060058365A1 (en) * 2004-08-06 2006-03-16 Kohn Leonard D Compositions and methods for treatment of colitis WO2006049304A1 (en) 2004-11-02 2006-05-11 Banyu Pharmaceutical Co., Ltd Aryloxy-substituted benzimidazole derivatives US20060134176A1 (en) * 2004-12-22 2006-06-22 Bausch & Lomb Incorporated Pharmaceutical delivery system and method of use US20060185678A1 (en) * 2005-02-03 2006-08-24 Bronnenkant Lance J Devices for delivering agents to a vaginal tract US8927005B2 (en) 2005-02-09 2015-01-06 Santen Pharmaceutical Co., Ltd. Liquid formulations for treatment of diseases or conditions US9381153B2 (en) 2005-02-09 2016-07-05 Santen Pharmaceutical Co., Ltd. Liquid formulations for treatment of diseases or conditions US9387165B2 (en) 2005-02-09 2016-07-12 Santen Pharmaceutical Co., Ltd. Rapamycin formulations and methods of their use US8367097B2 (en) 2005-02-09 2013-02-05 Santen Pharmaceutical Co., Ltd. Liquid formulations for treatment of diseases or conditions US8637070B2 (en) 2005-02-09 2014-01-28 Santen Pharmaceutical Co., Ltd. Rapamycin formulations and methods of their use US8663639B2 (en) 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions WO2006091871A1 (en) 2005-02-23 2006-08-31 Halozyme Therapeutics, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US7846431B2 (en) 2005-02-23 2010-12-07 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases EP3943501A1 (en) 2005-02-23 2022-01-26 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US10588983B2 (en) 2005-02-23 2020-03-17 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US7829081B2 (en) 2005-02-23 2010-11-09 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US20100196423A1 (en) * 2005-02-23 2010-08-05 Bookbinder Louis H Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases EP3045472A1 (en) 2005-02-23 2016-07-20 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases US9867828B2 (en) 2005-03-11 2018-01-16 Aminopterin Llc Aminopterin dosage forms US20070087406A1 (en) * 2005-05-04 2007-04-19 Pei Jin Isoforms of receptor for advanced glycation end products (RAGE) and methods of identifying and using same EP2399578A1 (en) 2005-05-17 2011-12-28 The Interthyr Corporation Methods and compositions for the treatment of autoimmune and inflammatory diseases associated with toll-like receptors WO2007037534A1 (en) 2005-09-30 2007-04-05 Banyu Pharmaceutical Co., Ltd. 2-heteroaryl-substituted indole derivative US20070161081A1 (en) * 2005-11-10 2007-07-12 Receptor Biologix, Inc. Hepatocyte growth factor intron fusion proteins US8658667B2 (en) 2006-02-09 2014-02-25 Santen Pharmaceutical Co., Ltd. Stable formulations, and methods of their preparation and use US8492400B2 (en) 2006-02-09 2013-07-23 Santen Pharmaceutical Co., Ltd. Stable formulations, and methods of their preparation and use US9452156B2 (en) 2006-03-23 2016-09-27 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions US8222271B2 (en) 2006-03-23 2012-07-17 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions US8486960B2 (en) 2006-03-23 2013-07-16 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions US20100055093A1 (en) * 2006-06-12 2010-03-04 Receptor Biologix Inc. Pan-cell surface receptor-specific therapeutics US20070293190A1 (en) * 2006-06-14 2007-12-20 Yuya Ota Remote control system and remote control method US8663633B2 (en) 2006-07-05 2014-03-04 Torrey Pines Institute For Molecular Studies Protease screening methods and proteases identified thereby EP3034607A1 (en) 2006-07-05 2016-06-22 Catalyst Biosciences, Inc. Protease screening methods and proteases identified thereby EP2402437A2 (en) 2006-07-05 2012-01-04 Catalyst Biosciences, Inc. Protease screening methods and proteases identified thereby EP2402438A2 (en) 2006-07-05 2012-01-04 Catalyst Biosciences, Inc. Protease screening methods and proteases identified thereby US9290757B2 (en) 2006-07-05 2016-03-22 Catalyst Biosciences, Inc. Protease screening methods and proteases identified thereby US8211428B2 (en) 2006-07-05 2012-07-03 Torrey Pines Institute For Molecular Studies Protease screening methods and proteases identified thereby WO2008044777A1 (en) 2006-10-06 2008-04-17 Banyu Pharmaceutical Co., Ltd. 2-pyridinecarboxamide derivative having gk-activating activity WO2008066131A1 (en) 2006-12-01 2008-06-05 Banyu Pharmaceutical Co., Ltd. Novel phenyl-isoxazol-3-ol derivative WO2008094476A1 (en) 2007-01-31 2008-08-07 Merck & Co., Inc. Substituted pyrano [2, 3 - b] pyridine derivatives as cannabinoid -1 receptor modulators US20100222394A1 (en) * 2007-09-28 2010-09-02 Kenichi Asakawa Method for producing pyrazol-3-yl-benzamide derivative US20100278801A1 (en) * 2007-10-16 2010-11-04 Shepard H Michael Compositions comprising optimized her1 and her3 multimers and methods of use thereof US20110009463A1 (en) * 2007-10-17 2011-01-13 Yuri Karl Petersson Geranylgeranyl transferase inhibitors and methods of making and using the same WO2009063821A1 (en) 2007-11-12 2009-05-22 Banyu Pharmaceutical Co., Ltd. Heteroaryloxy quinazoline derivative WO2009081782A1 (en) 2007-12-25 2009-07-02 Banyu Pharmaceutical Co., Ltd. N-pyrazole-2-pyridinecarboxamide derivative US9833498B2 (en) 2008-03-06 2017-12-05 Halozyme, Inc. Methods of treatment of collagen-mediated diseases and conditions US9775889B2 (en) 2008-03-06 2017-10-03 Halozyme, Inc. Methods of treatment of cellulite US10328130B2 (en) 2008-04-14 2019-06-25 Halozyme, Inc. Modified hyaluronidases and uses in treating hyaluronan-associated diseases and conditions EP3192525A1 (en) 2008-04-14 2017-07-19 Halozyme, Inc. Modified hyaluronidases for use in treating hyaluronan-associated diseases and conditions EP2662090A1 (en) 2008-04-14 2013-11-13 Halozyme, Inc. Modified hyaluronidases and uses in treating hyaluronan-associated diseases and conditions WO2009147990A1 (en) 2008-06-02 2009-12-10 萬有製薬株式会社 Novel isoxazole derivative US11389435B2 (en) 2008-09-15 2022-07-19 Biovista, Inc. Compositions and methods for treating epilepsy US8703947B2 (en) 2008-10-10 2014-04-22 Purdue Research Foundation Compounds for treatment of Alzheimer's disease US20110195978A1 (en) * 2008-10-10 2011-08-11 Purdue Research Foundation Compounds for treatment of alzheimer's disease WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents US8394807B2 (en) 2008-11-20 2013-03-12 Purdue Research Foundation Quinazoline inhibitors of BACE 1 and methods of using US20110230505A1 (en) * 2008-11-20 2011-09-22 Purdue Research Foundation Quinazoline inhibitors of bace 1 and methods of using US8859590B2 (en) 2008-12-05 2014-10-14 Purdue Research Foundation Inhibitors of BACE1 and methods for treating Alzheimer's disease EP3037529A1 (en) 2008-12-09 2016-06-29 Halozyme, Inc. Extended soluble ph20 polypeptides and uses thereof US8927249B2 (en) 2008-12-09 2015-01-06 Halozyme, Inc. Extended soluble PH20 polypeptides and uses thereof WO2010077297A1 (en) 2008-12-09 2010-07-08 Halozyme, Inc. Extended soluble ph20 polypeptides and uses thereof WO2010095767A1 (en) 2009-02-23 2010-08-26 Banyu Pharmaceutical Co.,Ltd. Pyrimidin-4(3h)-one derivatives US20110229451A2 (en) * 2009-03-06 2011-09-22 Halozyme, Inc. Temperature sensitive mutants of matrix metalloproteases and uses thereof WO2010102262A1 (en) 2009-03-06 2010-09-10 Halozyme, Inc. Temperature sensitive mutants of matrix metalloprotease 1 und uses thereof US20100284995A1 (en) * 2009-03-06 2010-11-11 Louis Bookbinder Temperature sensitive mutants of matrix metalloproteases and uses thereof WO2010104195A1 (en) 2009-03-11 2010-09-16 Banyu Pharmaceutical Co.,Ltd. Novel isoindolin-1-one derivative WO2010127452A1 (en) 2009-05-04 2010-11-11 The Royal Institution For The Advancement Of Learning/Mcgill University 5-oxo-ete receptor antagonist compounds WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents US9062057B2 (en) 2010-03-19 2015-06-23 Purdue Research Foundation CCR5 antagonists for treating HIV US8765166B2 (en) 2010-05-17 2014-07-01 Novaer Holdings, Inc. Drug delivery devices for delivery of ocular therapeutic agents EP3243385A1 (en) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents US9937335B2 (en) 2011-06-06 2018-04-10 Oak Crest Institute Of Science Drug delivery device employing wicking release window EP2717813A4 (en) * 2011-06-06 2014-11-05 Oak Crest Inst Of Science Drug delivery device employing wicking release window US9102105B2 (en) * 2011-09-13 2015-08-11 Vista Scientific Llc Method for forming an ocular drug delivery device US20130062809A1 (en) * 2011-09-13 2013-03-14 Vista Scientific Llc Sustained Release Ocular Drug Delivery Devices and Methods of Manufacture WO2013040501A1 (en) 2011-09-16 2013-03-21 Pharmathene, Inc. Compositions and combinations of organophosphorus bioscavengers and hyaluronan-degrading enzymes, and uses thereof US9540332B2 (en) 2011-12-28 2017-01-10 Allergan, Inc. Benzimidazole derivatives as selective blockers of persistent sodium current EP3184525A1 (en) 2011-12-28 2017-06-28 Allergan, Inc. 3-phenyl-5-ureidoisothiazole-4-caboximide and 3-amino-5-phenylisothiazole derivatives as kinase inhibitors US8859780B2 (en) 2011-12-28 2014-10-14 Allergan, Inc. Benzimidazole derivatives as selective blockers of persistent sodium current WO2013101926A1 (en) 2011-12-28 2013-07-04 Allergan, Inc. Benzimidazole derivatives as selective blockers of persistent sodium current US8969583B2 (en) 2011-12-28 2015-03-03 Allergan, Inc. 3-phenyl-5-ureidoisothiazole-4-carboximide and 3-amino-5-phenylisothiazole derivatives as kinase inhibitors US12037618B2 (en) 2011-12-30 2024-07-16 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US11952600B2 (en) 2011-12-30 2024-04-09 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12104184B2 (en) 2011-12-30 2024-10-01 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof EP3130347A1 (en) 2011-12-30 2017-02-15 Halozyme, Inc. Ph20 polypeptide variants, formulations and uses thereof US11041149B2 (en) 2011-12-30 2021-06-22 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12264345B1 (en) 2011-12-30 2025-04-01 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US10865400B2 (en) 2011-12-30 2020-12-15 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12110520B2 (en) 2011-12-30 2024-10-08 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12091692B2 (en) 2011-12-30 2024-09-17 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12123035B2 (en) 2011-12-30 2024-10-22 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12104185B2 (en) 2011-12-30 2024-10-01 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12054758B2 (en) 2011-12-30 2024-08-06 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12152262B2 (en) 2011-12-30 2024-11-26 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12018298B2 (en) 2011-12-30 2024-06-25 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US9447401B2 (en) 2011-12-30 2016-09-20 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12049652B2 (en) 2011-12-30 2024-07-30 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12077791B2 (en) 2011-12-30 2024-09-03 Halozyme, Inc. PH20 polypeptide variants with a modification at position 309 of the PH20 polypeptide and a method of making thereof US12060590B2 (en) 2011-12-30 2024-08-13 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US11066656B2 (en) 2011-12-30 2021-07-20 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US12195773B2 (en) 2011-12-30 2025-01-14 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof US10172854B2 (en) 2012-02-27 2019-01-08 Biovista, Inc. Compositions and methods for treating mitochondrial diseases WO2013142380A1 (en) 2012-03-22 2013-09-26 The Regents Of The University Of California Oncovector nucleic acid molecules and methods of use US10137104B2 (en) 2012-04-04 2018-11-27 Halozyme, Inc. Combination therapy with an anti-hyaluronan agent and therapeutic agent US9913822B2 (en) 2012-04-04 2018-03-13 Halozyme, Inc. Combination therapy with an anti-hyaluronan agent and therapeutic agent WO2013151774A1 (en) 2012-04-04 2013-10-10 Halozyme, Inc. Combination therapy with an anti - hyaluronan agent and a tumor - targeted taxane US9034870B2 (en) 2012-07-13 2015-05-19 Purdue Research Foundation Azaindenoisoquinoline topoisomerase I inhibitors WO2014031465A1 (en) 2012-08-22 2014-02-27 Merck Sharp & Dohme Corp. Novel azabenzimidazole tetrahydropyran derivatives WO2014062856A1 (en) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods US9278124B2 (en) 2012-10-16 2016-03-08 Halozyme, Inc. Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods WO2014093189A1 (en) 2012-12-10 2014-06-19 Merck Sharp & Dohme Corp. Methods of treating diabetes by administering a glucagon receptor antagonist in combination with a cholesterol absorption inhibitor US11077092B2 (en) 2012-12-10 2021-08-03 Merck Sharp & Dohme Corp. Methods of treating diabetes by administering a glucagon receptor antagonist in combination with a cholesterol absorption inhibitor WO2014096852A1 (en) 2012-12-21 2014-06-26 Coopervision International Holding Company, Lp Antimicrobial ophthalmic contact lenses WO2014096853A1 (en) 2012-12-21 2014-06-26 Coopervision International Holding Company, Lp Methods of Manufacturing Contact Lenses For Delivery of Beneficial Agents WO2014096854A2 (en) 2012-12-21 2014-06-26 Coopervision International Holding Company, Lp Ophthalmic devices for delivery of beneficial agents EP3151040A1 (en) 2012-12-21 2017-04-05 CooperVision International Holding Company, LP Antimicrobial ophthalmic lenses WO2014107745A1 (en) 2013-01-07 2014-07-10 Halozyme, Inc. Metal sensitive mutants of matrix metalloproteases and uses thereof WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents US10098836B2 (en) 2013-05-02 2018-10-16 Retina Foundation Of The Southwest Method for forming a molded two-layer ocular implant US10881609B2 (en) 2013-05-02 2021-01-05 Retina Foundation Of The Southwest Methods for treating eye disorders using ocular implants US10449145B2 (en) 2013-05-02 2019-10-22 Retina Foundation Of The Southwest Two-layer ocular implant WO2015003167A1 (en) 2013-07-03 2015-01-08 Halozyme, Inc. Thermally stable ph20 hyaluronidase variants and uses thereof WO2015009534A2 (en) 2013-07-16 2015-01-22 Allergan, Inc. Hcn inhibitors affecting ganglion cell function and visual function US11414489B2 (en) 2014-08-28 2022-08-16 Halozyme, Inc. Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor WO2016033555A1 (en) 2014-08-28 2016-03-03 Halozyme, Inc. Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor US9403803B2 (en) 2014-10-08 2016-08-02 Allergan, Inc. Indole-3-carboxamides as kinase inhibitors US9359336B2 (en) 2014-10-09 2016-06-07 Allergan, Inc. Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors US9650366B2 (en) 2014-10-09 2017-05-16 Allergan, Inc. Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors US10011593B2 (en) 2014-10-09 2018-07-03 Allergan, Inc. Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors US9296747B1 (en) 2014-10-10 2016-03-29 Allergan, Inc. Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2 US9969998B2 (en) 2014-10-14 2018-05-15 Halozyme, Inc. Compositions of adenosine deaminase-2 (ADA2), variants thereof and methods of using same WO2016061286A2 (en) 2014-10-14 2016-04-21 Halozyme, Inc. Compositions of adenosine deaminase-2 (ada2), variants thereof and methods of using same US11584923B2 (en) 2014-10-14 2023-02-21 Halozyme, Inc. Compositions of adenosine deaminase-2 (ADA2), variants thereof and methods of using same WO2016176634A1 (en) 2015-04-30 2016-11-03 The Regents Of The University Of Colorado, A Body Corporate Polycyclic indoline and indolenine compounds WO2019014398A1 (en) 2017-07-11 2019-01-17 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof US11168326B2 (en) 2017-07-11 2021-11-09 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof WO2019222435A1 (en) 2018-05-16 2019-11-21 Halozyme, Inc. Methods of selecting subjects for combination cancer therapy with a polymer-conjugated soluble ph20 WO2020014543A2 (en) 2018-07-11 2020-01-16 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof US12201653B2 (en) 2018-07-11 2025-01-21 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof US12226439B2 (en) 2018-07-11 2025-02-18 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof WO2020047161A2 (en) 2018-08-28 2020-03-05 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof US12012600B2 (en) 2018-08-28 2024-06-18 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof US11242528B2 (en) 2018-08-28 2022-02-08 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof US11779612B2 (en) 2019-01-08 2023-10-10 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof US12024709B2 (en) 2019-02-27 2024-07-02 Actym Therapeutics, Inc. Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment WO2020176809A1 (en) 2019-02-27 2020-09-03 Actym Therapeutics, Inc. Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment US12257184B2 (en) 2019-10-24 2025-03-25 Denis LaBombard Ocular device and drug delivery system, with case WO2021097144A2 (en) 2019-11-12 2021-05-20 Actym Therapeutics, Inc. Immunostimulatory bacteria delivery platforms and their use for delivery of therapeutic products WO2022036159A2 (en) 2020-08-12 2022-02-17 Actym Therapeutics, Inc. Immunostimulatory bacteria-based vaccines, therapeutics, and rna delivery platforms US20240065970A1 (en) * 2020-11-04 2024-02-29 Aerie Pharmaceuticals, Inc. Medical implant US12213913B2 (en) * 2020-11-04 2025-02-04 Alcon Inc. Medical implant WO2023168426A1 (en) 2022-03-03 2023-09-07 Enosi Therapeutics Corporation Compositions and cells containing mixtures of oligo-trap fusion proteins (ofps) and uses thereof WO2024091863A1 (en) 2022-10-25 2024-05-02 Starrock Pharma Llc Combinatorial, and rotational combinatorial therapies for obesity and other diseases WO2024186690A2 (en) 2023-03-03 2024-09-12 Enosi Therapeutics Corporation Oligo-trap fusion proteins (ofps) and uses thereof Similar Documents

RetroSearch is an open source project built by @garambo | Open a GitHub Issue

Search and Browse the WWW like it's 1997 | Search results from DuckDuckGo

HTML: 3.2 | Encoding: UTF-8 | Version: 0.7.4