DE2140557A1 - MEDICINE DELIVERY TABLET FOR A HUMAN EYEBALL - Google Patents

Description

PATENT LAWYERS

DR.E. WIEGAND DPL-iNO. W. NiiMANN

DR. M. KGHLER DIPL-IinG. C. GERNHARDT 2140557

MÖNCHEN HAMBURG

TELEPHONE: 395314 2000 HAMBURG 50, August 11, 1971

TELEGRAMS: KARPATENT ■ KONIGSTRASSE 28

w 2h 890/71 8 / sh.

ALZA Corporation. . . Palo Alto, California (V.St.A.)

Human eyeball drug delivery tablet

The invention relates to an eye insert for the delivery of medicaments to (*. <S eye over a longer period of time.

At present, diseases of the eye are treated by using ophthalmic medicines in liquid or ointment-like form. To be effective in many instances, the application or delivery of the therapeutic agent should be essentially continuous be. Such a continuous drug delivery cannot be achieved through the use of liquid or ointment-like dosage forms, even if these administered at intervals during the day and night. The periodic administration of these forms of medicine results in the eye receiving a large but unpredictable amount of the drug at the time of administration, however, the remedy is quickly washed away by tears, so that the eye remains without remedy until the next vesical treatment is left. Ointment-like dosage forms are available currently; only available in unsterilized form, and this is also a problem.

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At a very early stage, remedies were rolled into one water-soluble gel of glycerinated gelatine, which is dissolved or pearled, which is in the shape of a platelet or a Disc was brought. These platelets were on the inside Surface of an eyelid applied to the surface of the light means to feed. In use .jedoch the carrier consisting of glycerinated gelatin became in the tear fluid dissolved quickly, which led to the same effect as the liquid dosage forms. Such platelets did not form a dosage form for ongoing delivery. More information on these water-soluble dosage forms is provided below References to be found at Hemlnfton's Pharmaceutical Sciences, XIII, pages 5 ^ 7 and 5 ^ 8 (Mack Publishing Co., Easton, Pa., 1965}; Fishburn "An Introduction to Pharmaceutical Formulation", Page] i6 (Pergamon Press Ltd., New York City, N.J., 1965) and U.S. Patent P73406, March 6, JCS ^.

The invention provides an eyelid position, r "i" remedy able to deliver to the eye over a longer period of time and some of them are made of polymer! Material existing beer-semen bodies which is insoluble in tear fluid, has an imperforate surface and contains a remedy, that is delivered to the eye in a therapeutically effective amount by diffusion through the polymeric material will. The eye insert according to the invention can be in the conjunctival sac (cul-de-sac) between the dermis of the eyeball and the lid where it is held in place against the eyeball by the pressure of the lid.

According to the invention, an eye insert intended for the delivery of medicaments is designed so that it can be placed under a Eyelid, preferably the lower eyelid, can be arranged and held, and it is made of a polymeric material, manufactured, which has an imperforate surface and which the remedy due to diffusion through it Surface hLndurch gives off.

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BAOORIGfNAL

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Polymeric materials used to form the eye pad are pliable, biologically inert, insoluble in Tear fluid and non-allergenic. It is important, that the polymeric material is able to transfer the beneficial agent through its uninterrupted walls, and due to the diffusion of the medicinal product or the medicinal solution through the material walls. By exploiting the diffusion mechanism to deliver the remedy the eye can control the speed of the remedy release with Accuracy and reproducibility can be controlled. In that case, the selection of the polymer material depends on the particular one Light means and the particular form of remedy to be used in the device.

Examples of materials for making the eye insert include: hydrophobic polymers, such as plasticized or non-plasticized Polyvinyl chloride, plasticized polyamide (nylon), non-plasticized soft polyamide, plasticized Polyethylene terephthalate and silicone rubber, as well as hydrophilic polymers such as the hydrophilic hydrogels from Acrylic and methacrylic acid esters! (as described in U.S. patents ? 976 576 and 3 ?? o 960 and in the Belgian patent 7ol 815), modified collagen, Overlinked hydrophilic polyether gels (as described in US Pat 3 4? 9 oo6 are described), overlinked Polyvinyl alcohol and cross-linked, partially hydrolyzed polyvinyl acetate. When plasticizers or plasticizers used to give the polymer flexibility, Various plasticizers known in the art can be used, e.g., long chain fatty amides, higher Alcohols and dioctyl phthalate.

For those skilled in the art it is apparent that many of the for For purposes of the invention, suitable hydrophilic polymers tear fluid absorb and form a hydrogel with it. Tear fluid that enters the polymeric structure around swollen Forming hydrogel molecules dissolves that within the polymer Body located remedies, and the resulting drug solution then diffuses out of the hydrogel

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structure outwards. Hence, the term used here is intended to be "Diffusion" includes both the movement of a beneficial agent through an imperforate polymeric body and the. Include movement of a healing agent solution through an imperforate body. The one here continues in terms of appropriate As used in polymeric materials, the term "insoluble in tear fluid" means the polymeric materials are not dissolved or washed out by the action of the tear fluid, but absorb the tear fluid can to form a swollen hydrogel.

Any medicaments useful for treating the Eye and the tissues surrounding it. It is also convenient to use the eye and the tissues surrounding it as a Use the entry point for circulatory medicines that circulate in the bloodstream and a pharmacological Produce an effect in a location which is remote from the point of application of the eye insert. Therefore, in the Eye pad according to the invention also includes medicinal products which are applied over or around the eye Tissues enter the bloodstream but cannot be used to treat the eye itself.

Suitable remedies that can be used for eye therapy using the eye insert include, without limitation: Antiinfectants such as antibiotics, including tetracycline, "chlortetracycline, bacitracin, neomycin, polymyxin, Gramicidin, ocytetracycline, chloramphenicol and erythromycin; Sulfonamides, including sulfacetamide, sulfarnethizole, and Sulfisoxazole; Antiviral agents, including idoxuridine and other anti-infectives, including nitrofurazone and sodium propionate; Antiallergic drugs such as antazoline, Methapyrilen, cblorpheniramine, pyrilamine and prophenpyridamine; Anti-inflammatory agents such as hydrocortisone, hydrocortisone acetate, Dexamethasone, dexamethasone-21-phosphate, pluocinolone, medryson, prednisolone, prednisolone-21-phosphate and prednisolone

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acetate decongestants such as phenylephrine, naphazoline and tetrahydrazoline; Pupil constriction agents and anticholinesterase agents, such as pilocarpine, eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholine iodide and demecarium bromidej Pupil dilatants such as atropine sulfate, cyclopentolate, homatropin, scopolamine, tropicamide, eucatropin and oxyamphetamines and sympathomimetics such as epinephrine.

The remedies can be in various forms, such as uncharged molecules, components of molecular complexes or non-irritating, pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, phosphate, I. Nitrate, borate, acetate, maleate, tartrate, salicylate, etc. The following can also be used: simple derivatives of medicinal products (such as Xther, Ester, Amide, etc.), the desired holding and release characteristics, but due to the body pH, Enzymes, etc. can be easily hydrolyzed.

The amount of medicament included in the eye insert varies considerably depending on the particular medicament, the therapeutic effect desired, and the length of time for which the eye insert is used. Since the eye insert is intended to provide complete dosage amount for eye therapy only during a certain period, for example 24 hours, t is no critical upper limit of the amount of the 'included in the apparatus remedy exists, because if the device and discarded removed it makes little difference whether some remedy remains in the device. The lower limit depends on the activity of the beneficial agent and its ability to be released from the device. It is therefore not possible to specify a specific range for the therapeutically effective amount of the lightening agent included in the device. However, an amount of 1 microgram to 1 milligram of the remedy is typically included in the ocular elbow.

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In either case, the polymeric material used to form the eye pad is considered to be tolerable with a particular remedy and its ability to diffuse this remedy with an appropriate one Enable speed over a longer period of time is selected. Specific but non-limiting examples of combinations of medicaments and polymers for use for the formation of the eye insert are: (1) Chloramphenicol, enclosed in polyethylene terephthalate, which is with higher alcohols plasticized, (2) promethazine trichloroacetate, encased in polyvinyl chloride, which is dioctyl phthalate is plasticized, (j5) chloramphenicol, which is contained in polydimethylsiloxane rubber fully dispersed, (4) pilocarpine or pilocarpine perfluorobutyrate included in Polyvinyl chloride plasticized with dioctyl sebacate and (5) dexamethasone included in nylon-66, the one with higher Alcohol is plasticized.

The eye insert can be made in any convenient shape that will comfortably hold it in the conjunctival sac enables. It is important, however, that the device not have any sharp, jagged, or rough edges that lead to it inflammation of the delicate tissues of the eye. The eye inlay can be elliptical, honeycomb-shaped, be rectangular, etc. Their cross-section can be concave-convex, rectangular, etc. Because the eye insert is flexible and essentially takes on the configuration of the curvature of the dermis of the eye in use, is the original shape the device is of no particular importance.

The dimensions of the device can be within wide limits vary. The lower limit of the size of the device is determined by the amount of the particular remedy given to the Eye and the tissues surrounding it is to be supplied to the desired evoke pharmacological effect, as well as by the smallest device that is in the eye

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The upper limit of the size of the device is determined by the limited space within the conjunctival sac that can conveniently and conveniently be filled with an eye liner. Typically, the eye liner is k to 20 mm, a width of 1 to 12 mm and a thickness of 0.1 to 1 mm. It preferably has the shape of an ellipsoid with a size of 6 × 4 × 0.5 mm.

The eye pad is a sealed container that has walls made of polymeric material and is located in its inner chamber the medicament or the medicament dispersed in a carrier is incorporated. Such a container has a circular shape or elliptical cross-section and is tapered at the ends. The remedy can be found in the eye insert on many Wise to be included. It can be any of the encapsulation, Bonding and coating processes are used as are common in the art.

Reference is now made to Figures 1 and 2 of the drawing. .

To use an eye insert Io designed according to the invention (which is shown in dashed lines in FIG. 1), it is arranged in the sack 11 of the conjunctiva 12 between the dermis 1J> of the eyeball 14 and the lower lid 15. The eye pad Io is held in place by the pressure of the lower lid 15. When the eye inlay Io is under the lower lid 15, it is in a comfortable position for the user and it does not step either during sleep or during normal eye movements. in contact with the cornea 16 of the eyeball. Once the eye inlay Io is in place, it acts as a drug reservoir which gradually delivers the drug 17 to the eye and the surrounding tissue. The remedy exiting the eye inlay by diffusion is released by the flow of tear fluid and the closing and opening movements

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the eyelid is transported to the eyeball 14. By using the eye insert, the eye is continuously bathed with the therapeutic agent 17 for a certain period of time. Normally the eye insert Io is left in place for a period of 2k hours, so that the full dosage amount for eye therapy is delivered over this period of time. In the course of use of the eye insert, its polymeric body 18 will not be dissolved in the lacrimal flow or washed out into it, and thereby a predictable and reproducible dosage range is made possible.

The eye insert according to the invention thus offers numerous advantages. Because the eye pad is made of a polymer material is formed, which is insoluble in tear fluid they are not dissolved or washed out in tears in the course of the therapeutic program. This allows that precisely control therapeutic program and release the prescribed amount of cure with accuracy. The fact, That the eye pad releases the remedy by diffusion is extremely important as this is also a tight control of the Allows speed with which the remedy is released from the polymer.

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Claims (6)

2U0557 claims 1. drug delivery tablet for a human eyeball, characterized in that it has a drug supply which is enclosed in an inner chamber of a flexible, imperforate, continuous surface having, sealed container made of non-allergic, tear-insoluble polymeric material that the container is formed from a polymer which controls the amount of medicine released to the occurring by diffusion flux of the beneficial agent from the reservoir to the g eye with a controlled, predetermined and reproducible rate over a prolonged period of time to be measured continuously, that the container in the Conjunctival sac is insertable between the sclera of the eyeball and an eyelid where it is held in place against the eyeball by the pressure of the eyeball and that the container has an outline and cross-section such that it substantially resembles the configuration of the curvature of the sclera can assume that the medicament is one which, due to diffusion, can be transported through the uninterrupted walls of the container, and that the container is designed and arranged in such a way that it delivers the medicament to it after being applied to the eyeball, wherein the medicament leaving the container by diffusion I is transported to the eyeball by the flow of tears and the opening and closing movements of the eyelids. 2. Tablet according to claim 1, characterized in that the polymeric material forming the container is selected from the group which includes the following substances: plasticized or non-plasticized polyvinyl chloride, plasticized polyamide (Nylon), non-plasticized soft polyamide, plasticized Polyethylene terephthalate, silicone rubber, hydrophilic hydrogel of an acrylic or methacrylic acid ester, modified Collagen, cross-linked hydrophilic polyether gel, 3 0 9 8 0 9/1105 2U0557 - Io - cross-linked polyvinyl alcohol and partially hydrolyzed, Cross-linked polyvinyl acetate. 3. Tablet according to claim 1 or 2, characterized in that that the remedy is an ophthalmic remedy. 4. Tablet according to claim 1 or 2, characterized in that the remedy is a remedy acting on the system is, which reaches through the eye in the blood stream and on causes a pharmacological effect in a location remote from the eye. 5. Tablet according to one of claims 1 to h, characterized in that it has a circular cross-section and is tapered at its ends. 6. Tablet according to one of claims 1 to 4, characterized in that that it has an elliptical cross section and is tapered at its ends. - 7 · tablet that it has mm according to one of claims 1 to 6, characterized in that a length of 4 to 2o mm, a width of 1 to 12 mm and a thickness of o, 1 to the first 309309/1 1 05