CA1206049A

CA1206049A - Osmotic device for physiological applications

Info

Publication number: CA1206049A
Application number: CA000437694A
Authority: CA
Inventors: Paul E. Michelson
Original assignee: Individual
Current assignee: Individual
Priority date: 1982-09-30
Filing date: 1983-09-27
Publication date: 1986-06-17
Also published as: EP0120937A4; ES286420U; IT1208983B; IT8312631A0; JPS59501897A; WO1984001297A1; IL69854A0; ES286420Y; EP0120937A1

Abstract

ABSTRACT
An osmotic device for immersion in a physiolo-gical fluid, including a semipermeable sheath defining a fully enclosed cavity and being imperforate except for a plurality of pores for permitting the flow of the physio-logical fluid into the cavity. At least one macromole-cule is disposed within the cavity and has a size larger than the pores in the sheath so that the macromolecule is prevented from leaving the cavity when the device is immersed in the physiological fluid, such physiological fluid being caused to flow into the cavity through the pores under the influence of osmotic pressure. The cavity will always contain a molecular concentration greater than the molecular concentration of physiological fluid surrounding the sheath.

Description

OSMOTIC DEVICE FOR PHYSIOLOGICAL APPLICATIONS
Technical Field The present invention relates to an osmotic device for physiological applications, ~uch ~s an impxoved delivery system for the time release ~f physiologically active agents, and an improved lens system which utilizes fluid as it~ primary lens medium.
Background Art In recent years numerous devices hav~ been 10 devised which utilize osmotic flow for various physiolog-ical applications. For example, both UOS. Patent No.
4,26$,874 to 13Osen et aî and U. S. Patent No. 4,298,003 to Theeuwes et al disclose methods and devices for the delivery of a drug where, as a result of ~smotic flow, fluîd passes through a semipermeable membrane and forces an insoluble drug or a solution of a soluble drug out of the device through an enlarged opening or passageway.
The m~mbrane of these devices allows the 1ux of water only7 not the druy. The drug is ~orced out, under the influence of osmosis, through the enlarged opening or pa~sageway which is separately drilled in the deviees and whose size is ~rder~ of magnitude larger than the pores -o~ th~ membrane. U. 5~ Patent No. 3,832l458 reveals a devic~ in which a silicon polymer wall is utilized to vary permeability to an internal active agent. The permeability is adjusted by ~abricating the wall with varying amounts of N-vinyl~pyrrolidone. While thi~, device represents an improved drug delivery technique7 it has a significant disadvantage in that i~ represents a f irst order delivery system in which ~he drlving force of drug delivered to the outside is the ~esult of the internal concentration of drug alone. Thus the drug will be delivered a~ an initial rapid rate fol-lowed by a significantly lower rate until the active agent is expended.
U.SO Patent No. 4,30g,996 by The~uwes discloses a somewhat different mechanism for delivery of drugs whereby a separate compartment filled by a net osmotic inflow is utilized to expand against a 1exible internal partition which forces the active a~ent out o a second compartment through a microporous ~truc~ure thus attempt-ing to approximate a ~t~ady delivery rate.
Such prior art drug delivery devices are ei~her ov~rly complex~ adding to the cost of thP devices, or unable to control the precisP drug delivery rate. The ~smotic device of the present invention overcomes these drawbacks by providin~ a drug delivery sys~cm which is flexible in that there are numerous variable~ which can be modified to control the delivery rate of the drug.
In another application o the osmotic device according to the invention, ~n improved lens is provided which utilizes fluid as its primary lens medium. The osmotic device according to the present invention is especially suited for use as an ocular lens, and the present invention further includes an improved method for the insertion of such an ocular lensl It has long been recogni~ed that ocular lenses made of glass or substanti~lly rigid plastic resul~ in irritation discomfort and alteration of the normal coxneal physiology. Therefore, attempts have been made to reduce these effects by using softer, more permeable lens materials, particularly in the area of contact lenses. For example, ~S. Patent No. ~,241,415 to Moulton disclo!3es an ophthalmic lens having a ~upporting ~ortion formed of a thin~ soft, pliable and slightly plastic material.
In recent years; so calle~ ~'soft" contact lenses have been manufactured which utili~e hydrogels ~s lens mat~rials to reduce eye irrltation and discomfort~

For example, in U~S. Patent No. 4,123,408 to Gordon, there i8 disclosed a contact lens of a hydrogel compo-sition wherein the hydrogel utilizes a polymerized water-insoluble, water-swellable polymer composition.
U.S. Patent No. 4,153,349 'co Wichterle al50 discloses a method of making hydrogel contact lenses having improved lens properties. While ~Isoft~ contact lenses have reduced irritation and discomfort experienced while using prior art lenses, the soft contact lenses~ while softer than prior art rigid lenses, must be sufficiently rigid to maintain the desired lens shape when utilized by the wearer and therefore a significant amount of foreign matter is introduced into the eye.
Any time foreign matter is introduced into the eye, there is a potential problem that irritation and discomfort will result even if the material is relatively soft. It will also hindex the passage of oxy~en, nutri-en~s, other gases and metabolites between cornea and tear film and thus potentially alter the normal physiology and 23 clarity o the cornea. The ideal lens would utilize body fluids, such as lachrymal fluids, ~o form the desired lens and therby completely eliminate the need for intro-duction of foreign material into the eye. However, since it is not possible to retain such fluid in a desired lens eonfigration, at least some type of structural member mus~ be included to form the fluid into the shape of the lens.
The use of fluid in conneetion with ocular devices has been generally relegated to purposes other than the formation of a primary lens medium. For exam-ple, U.S. Patent No. 3,710/796 to Neefe discloses an opthlalmic dr0ssing where a drug is impregnated into a transparent osmotic permeable material which serves to define the shape of the device. Diffusion of the drug out of its impregnated or dispersed state within this homogeneous polymer apparently determines the drug delivery rate, European Patent Application No.~32,$17 published July 29th, 1981 discloses a lens which permits ~LZ~

the configuration of the device to a cornea by utilizing an insert filled with physiologically compatible fluid such as lachrymal fluid~ However, the lens utilizes a soft contact material, not the fluid, as the primary lens medium.
DISCLOSURE OF THE INVENTION
It is an object of the present invention ~o provide an imprcved osmotic device for a variet~ of physiolo0ical applications.
10It is another object of the present invention to provide a new and improved system for delivering physiologically active agents.
It is a further object of the present invention to provide a new and improved system for the delivery of a physiologically active agent which is less complex than prior art devicesO
It is an additional object of the present - invention to provide a new and improved system for the delivery of physiologically active agents which permits more control and flexibility in the amount and rate of delivery of active agents than prior art devices,.
It is another o~ject of the present invention to provide a new and improved system for the delivery of physiologically active agents which utili~es the pores of a semipermeable membrane ~o deliver the active agent to a surrounding fluid environment.
It is yet another object of the present inven-tion tv provide a new and improved lens.
It is a further object of the invention to provide a new and improved lens which utili~es fluid a5 the primary lens medium.
I~ is an additional object of the present invention to provide a new and improved lens which utilizes fluid as the primary lens medium and is particu-larly suited for use a~ an ocular lens.
It is another object of the present invention to provide a new and improved lens which utili~es Eluid g~

as the primary lens medium while keeping the structural material which forms the fluid in the shape of a lens to a minimum.
It is still a further object of the present invention to provide a new and improved lens which utilizes a semipermeable membrane to maintain a fluid body in a desired lens shape.
It is yet a further object of the present invention to provide a new and improved lens which utilizes a semipermeable membrane to maintain a fluid body in a desired lens shape and which retains the desired shape as a result of osmotlc flow between the outside environment and the fluid body.
It is an additional object of the present invention to provide a new and improved lens which will permit the delivery of physiologically active agents.
It is a further o~ject of the present invention to provide a new and improved lens which will permit the maximum exchange of gases, nutrients and metabolites between cornea, lachrymal iEluid and the atmosphere, thus minimally compromising normal physiologyr Another object oE the present invention is to provide a physiological lenticule capable of being introduced into the substance of the cornea with minimal disruption of its normal physiology while at the same time, altering significantly its ~hape and refrac~ive power.
Yet another object of the present invention is to provide a new and improved method of placing a lens in the eye by insertion through a minimal incision.
Additional ob jects and advantayes of the present invention will be set forth in par~ in the description which follows and in part will be obvious from the description or can be learned by practice of the invention. Thle objects and advantages are achieved by means of the processes~ instrumentalities and combina-tions particulclrly pointed out in the appended claims.

To achieve the for~going objects and in accord-ance with its purpose, the present inven~cion proviæes, in îts broad~st aspeck, an 05motic device for immersion in a physiol~gical 1uid~ The device includes a ~emipermeable ;heath def ininy el :~ully enclos~d c:avity and bPing imper-forate except for a plurality of pores for permitting the Plow of the physi~:>logical f luid into ~he cavity. At least one macromolocule is located within the cavity and has a ~ize that is larger than the pores in thR sheath so that the macromolecule is prevented from l~aving the cavity when the osmotic device is immersed in the physio-logical fluid whereupon ~he physiological fluid surround-ing the sheath is allowed to flow into the cavity through the pores under the influence of osmotic pressure and the moleclllar concentration of the physiologic~l fluid within the sheath is maintained greater than the molecular concentration of the physi~logical fluid outside the 5 heath.
In one em~odiment of th~ present invention a ~ystem is provided for the controlled delivery of a physiol~gically ac~ive agent to a fluid ~nvironment comprisin~ a semipermeable sheath having a plurality of pore~ and being imperforate exc~pt for the plurality of pores and defining a ful:ly enclosed cavity or holding a phy~iologi~ally active a~ent. A physiologically active .~gent i~ contained in t~e fully enclosed cavity for delivery to a luid environment, the plurali~y of pores being æized to permit both the flow of fluid from the fluid environment through the semipermeable ~heath into th~ cavity and the flow of fluid and physiologically active agent in solution ~ut of the cavity to the fluid s~nvironment whereby the physiologically ac~ive ag~nt i~ delivered frs:)m the semipermeable sheath exclusively through the plura1ity of pores.
In another embodiment of the present invention lens is provided comprising a semipermeable transparent sheath having opposite anterior and posterior por~ions joined at t.heir edyes and forming a clo~ecl interior space ~$6~

between themselves. A body of liquid is provided within the sheath, fills the interior space and constitutes a lens whose anterior and posterior surfaces are boundecl by the anterior and posterior portions of the sheath, respectively. Means are provided, in the body of liquid for producing within the interior space a concentra~ion which is greater than the concentration of a liquid medium in association with which the lens is to be used, in conseguence of which when the lens is in contact with such medium, the interior space will be kept filled with liquid under the influence of osmosis which causes the flow of liquid from the exterior of the sheath to the interior thereo$, whenever the interior space i5 le~s than full.
An alternative embodiment of the present invention provides a lens in the form of a contact lens comprising ~ concave semilpermeable transparent element adapted to seat on a human cornea to form therewith a closed interior space which ~ontains a body of physiolog-ical solution produced by the wearer of the element andthe body of liq~id constitutes an op~.ical lens whose anterior surface is bouncled by the element and whose posterior surface is bounded by the cornea of the wearer~
Means carried by the element at its interior is provided for producing within the interior space, when the same contains the body of liquid, a concentration which i5 greater than the concentra~ion of the physiological solution produced by the wearer of the con~act lensl in consequence of which when the element is worn on the cornea, the interior space will be kept filled with liguid undex the influence of osmosis which causes the flow of liquid from the exterior of the space to the interior thereof whenever the interior space is less than Furthermore, the present invention provides a method of locating an intraocular lens into an eye comprisincJ the steps of providing a dehydrated semiper-meable transparent sheath having opposite anterior ancl ~2~

posterior portions joined at their edges and forming a closed in~erior space between themselves and means within the interior space for producing within the interior spacing a concentration which is greater ~han the concen-tration of the physiological solution produced by the wearer of the lens, in consequenc~ of which when the sheath i5 worn by the wearer, the sheath will hydrate such that the interior space will be kept f illed with liquid under the influence of osmosis and therby form a 10 lens, making an incision for insertion of the dehydrated semipermeable sheath into the eye and then inserting the dehydrated semipermeable ~heathing into the eye whereby the dehydrated ~emiperm~able sheath will contact the physiological solution produced by the wearer and hydrate to form a lens.
While the osmotic device of the present inven-tion is particularly suited for an ocular lenst it is also suitable for any lens which is intended to ~e utilized in a fluid environment. In addition, the

2~ osmotic device o ~he present invention, whether or not it is in the form of a lens, permit~ the dispensing of phyRiologically active age!nts over a sustained period of time when the device is immersed in a physiological fluid BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a perspective view of a device according to the invention.
Figure 2 is a sectional view along the section line II II in Figure 1.
Figure 3 is a plot of the drug del.ivery rates of devices according to the invention.
Yigure 4 is a perspective view of an altern-ative embodiment of a device in the form of a lens according to the invention.
Figure S is a sectional YieW of the alternative embodiment oE the lens shown in Figure 4 in place on the coxnea of the wearer.
Figure 6 is a perspective view of an eye in ~9~

partial ~ection showing an al~erna~ive emb~diment ~f the invention partially inserted therein.
BEST MODES FOR CARRYING O~T THE INVENTION
_ _ _ _ _ _ ___ ____ _ ___ _ ___ _____ ___ _____ The osmotic device according to the invention will firs~ be described in ~h~ context of a delivery system f~r physlologically active agents.
In accordanee with the invention, as ~hown in Figure 1, an osmotie deviee 10 which is generally of circular configuration, but whose shape may vary as 10 appropria~e for differing sites of application, consists o a ~emipermeable sheath 19 which is made of two ~hin ~heets 12 ~nd 14. The thin ~heet~ 12 and 14 ~re bound along th~ir respective edges to form a sheath with an outside edge 16. As will be ~pparent her~after~ the osmotic device, when employ~d as a deliv~ry system accordin~ to the invention, is intended to be used in a fluid environment with suffi.cient fluid present ~o enable the ~y~tem to operate as intended. Furthermore, as with the prior art devices, the system according tc~ the 20 invention, i5 parti~l~larly suitable for the delivery of active agerlts to animals and may be located with respect to the animal to be treated by positioning or innplanting the ~ystem in a variety of locations such as ~he animals rectum or gastrointe~tinal tr~ct~ tc~
As can be ~een in Figure 2, thin sheets 12 and 14 define a cavity 18 which i5 intended ~o contain a physiologically active agent~ Thin sheets 12 and 14 are provided with a plurality of pores in ordsr to be ~emi-permea~le and permit the passage of fluid the~ethrough.
The emip~rmeable thin ~heets 12 and 14, when joined to form edge 16, result in a semipermeable ~heath, 'rhe present invention utilizes the principle of osmotic 10w which results from a difference in molecular concentration being pre~ent across a semipermeable membrane ~
According to this embodiment of ~he invention, cavity lB will contain at least a physlologically active agent which wi:ll go into solution with fluid which will 6~

enter CAVity 18. The ph~siologically active agent may o~
may not be fully soluble ~s long as it can be delivered from device 10 at a suitable and pr~dictable rate. As will be described in more detail hereinafter, in a preferred embodiment of the invention, a macromolecule is also present in cavity 1~. The term macromolecule i5 in~ended to mean a large molecule such as a protein, carbohydrateJ rubber or other natural or synthetic higher polymer.
The pre~ence of an aetive agent in cavity 18 results in a net molecular concentration gradiçnt being set up between the cavity 18 and the fluid environment in which the lens is used. Thi~ net molecular concentration gradient will result in flow of fluid from the fluid environment through the semipermeable sh~ath into cavity 18. This flow of fluid, generally referred to as osmotic flow, results from the net higher molecular conc~ntration or net higher osmotic pressure which is present in cavity 18 due to the presence of a physiologically active agent alone or the physiologically active agent and the macromolecule. That is, the body of fluid inside the ~emipermeable sheath is h~ypertonic with respec~ ~o the fluid outside of the semipermeable sheath, i.e., the fluid inside the semipermeable sheath has a higher osmotic pressure than the fluid outside the semipermeable sheath.
When measured at any given instance, the osmotic pr~sure inside cavity 18 will be higher than that of the fluid surrounding the device and, therefore, there will be a net inward 10w of fluid~ However, over a period of time fluid cvntinuously enters and leaves cavity 18 whieh results in a dispersion of the active ayent from cavity 18~ While there will be continuing "steady state;' flux of fluid between the environment and internal fluid o the device, the net inElow ~f fluid volume will occur in the initial states under the inElu-ence of osm~sis until the ~smotic pressure and 1uid inflow result in the device achieving i~s natural pre-~2~

molded configuration. The burst strength of the encapsu-lating polymer film and its ~eal exceed the maximum achievable osmotic pressure by at least 6everal orders of magnitude. The continuing steady-state flux of fluid across the walls of the device will result in the disper-sion of any active agent whose molecular size is such as to allow passage through the preselected pore diameter of the membrane wall.
The osmotic flow which results due to molecular concentration diff~rences i6 independent for each mole-cule involved. For example, in the above example if the macromolecule, designated A, and another molecule, designated B, were added to eavity 18, and went into solution and became part of the body of liquid in cavity 18, molecule B wc>uld set up a concentration gradient across the semipermeable sheath independsnt of the gradient present as a result of macromolecule A. The osmotic flow resulting from the presence of molecule B
would be independent of the osmotic flow resul~ing from the presence of macromolecule A~
Preferably, in this embodimen~ of the invention a macromolecule would be complexed with the physiol~gical agent and the macromolecule select~d such that it would be lar3er than the pores of the semipermeable æheath, yet the complex would decay over a period o time thereby allo~ing the active agent to slowly disperse from the semipermeable sheath.
The macromolecule~ according to the invention, may be selected from any class of compounds with molecu-30 lar weight and configuratic)n sufficiently large to beexcluded passage of the dssired pore si~e. Generally suitable are the dextrans, amylopectins ~hydroxyethyl-starch)0 polyvinylpyrrolidone/ polyethylene glycol~
albumin and various ~ther soluble polymers and/or pro-teins. Alternatively, emulsions with droplets containing active agent can be utilized as well, Microemulsions with droplets of a ~iame~er range 3.01 to 0.1 microns are transparent and optically clear and thus, preferable or optical ~;ystems whereas macroemulsions with droplet of ~ize tl.l to 1 or 2 micrometers may be sati~factory in other uses.
The ac~ive agents suitabie for use in ~onnec-tion with the present invention include for examples:
oxygen, preferentially bound to fluorocarbons; salicy-lates, catechols, halo~ens~ barbiturate~ or ~ther com-pounds complexed to a macromolecule such as polyethylene ~lycols,o antibiotlcs such as chloramphenicol, sulfa or other medications complexed with a macromolecule -~uch as polyvinylpyrrolidone; antiepileptic medications such as phenytoin complexed ~o albumin; antihistamines, quinine, procaine Gr other compounds complexed to a ~acromolecule ~uch as sodium carboxymethylcellulose; salicylates complexed to the antibiotics oxytetracycline or tetracy-cline or other compounds complexed to a macromolecule such as salicylates or other macromol~cules could be utilized ~uch as caffeine or albumin~ The above identi--fied complexes have well known as~ociation ~onstants.
See ~enerally ~? 16th Editiony Arthur Osol, Edi.tor, Mack Publishing Co. 1~80, pp, 182-193 and Physical Pharmacy, 2d Edition, Martin et al, Lea ~ Febiger, 1969, pp, 325-352.
A given delivexy rate of active agent and/or , complexing molecule can be achieved through selecti~n of I appropriate membrane pore size, density, environment~l conditions and binding molecule. ~ctive agent and binding molecule form a molecular complex with an affin-ity for each other which can be expres~ed as a~ asocia-tion constant, ~n ~asily determined quantity related to I concentration and physicochemical environment. This ¦ constant is directly proportional to the eoncentrativn of ~ ~he complex and inversely proportional to ~he product of ! the concentrations of aetive agent uncomplexe~ ~nd , binding molecille uncomplexed, It can thus be seen ~hat I if ~ nondiffusable binding molecule is chosen, the further dampening of a potentially rapid or exponential rate of d~livery of active agent can be achieved. }n 1~
~imple form, if the ass~ciation constant is represented as R, the molar concentration of ~he drug as (D)~ the binding molecule concentration as (B)~ and ~he bound complex a~ ~B-D), the following xepr~sent~ ~h~ relation-æhip described:

K = (B-D~
~B)(D) The thickness of the semipexmeable sheet material, utilized in connection with the invention, will depend on a number of fact~rs and is directly related to the int2nded use of the delivery system. Generally, the ; membrane thickness will range from 5-10 micrometers, depending upon the materi~l used and the intended conf ig-uration ~nd concentration gradient. Sheet material could be selected from cellulose acetate, cellulose acetate Ibutyrate, cellulose triacetate, pc~ly 1, 4 butylene t~rephthalate ~such as MYLAR ~, polymethylmethacry-late, polypropylene Isuc:h as CRYOVAC ~, polystyrene, polyvinyl acetate, polyvinyl chloride, polyvinyl fluoride polyvinylidene chloride ~such as SARAN~), polycarbon-ate or silicon-polycarbonate copolymers (such as NUCLEPORE ) and other~.
The sheet material can be made porous in a variety of ways. For example, ~he technique of nuclear track etching can be used, in which the polymer f ilms are exposed to radioactive decay particles and products and then treated chemically to ~etchl' permanently the tracks of the particles through the $ilm, thus creating p~res of a si~e and density determined by the e~posure time and ~tching process. The particle dose determines the hole 30 density while the pore diameter is a function of etching time. Th* specific particles, dose, etchants, and other conditi~ns to achieve desired pore ~i2es and densi~y for the aforementioned polymer ilms are well kn~wn in the prior art. See Nuclear Tracks ~n Solids, Principals and cati~ns, R. L~ Fleischer et al, University of California Press, 1975. For e~cample, polyc:abonate 6~

f ilters (such as MUCLEPORE ) are produced by - exposure to 1~ fol lowed by s :>dium hydroxide etching.
Polyvinylidene chloride (such as SARAN ) can be made microporous by exposure to fi~sion fragments cf C:alifor-nium 252 followed by etching with pota~sium permang-anate at 55 degrees Centrigrade, As an alternative to nuclear tracking e~:ching, the newer advanced lasers such as frequency-doubled Neodymium-YAG, Excimer, ~unable dye or other lasers may be used to produce pores of the 10 desireà æize and density.
Pores may al~o be created by formin~ membranes as integrated ~heets of polymer con~aining 'Ipore-orm-ers~ n molecule~ which sub~equently can be leached or disso:Lved out, leaving ~ predict~ble pore size. The leaching or di~solution can be accomplished prior to use or so selected to occur in the environment of use~ For example, certain polymer ilms made of various polycar-bonates, polyamides, or polyesters can include such pore ~Eormers as lithium carbonate, calcium phosphat~, and 20 various poly~accharidç~s, ~uch as mannitol~ CARBOW~X, etc, The microporous paths th~n fill with a medium, compatible with or identica.l to the medium of the envir-onment in which active agent, complexing (binding) molecule and eomplex are soluble, thus permittinc~
diffusion of active agent and fluid medium out of cavity 18 and the generation of an osmo~ic gradient across semipermeable sheçts 12 and 14. These above processes, and others for creating micr~porous membranes, are noted in the prior art literature and are compiled in such works as ~nthetic Polymer Membranes, ~. E, Resting, McGraw-Hill Inc., 1971~
The pore size will prefera~l~ rang~ between 50 Angstroms diameter to 1,000 Ang~stroms; however, i~ may be possible to have pore sizes smaller than 50 Angstroms, if desired. The pore size is selected depending on the molecular weight and configuration of the macromolecule.
For exampleJ ~ pore sixe of approximately 60 ~ngstroms will exclude a molecule having a molecular w~igh~ of about 10,0009 A 100 Angstrom pore ~ize will exclude a ~.

6~

molecule having a 100,000 molecular weight. The exact three dimensional configuration of the molecules may, of course, produce exceptions. Pore density wou~d be on the order of 105 to 101 per square cm; however, de-pending on the appli.cation of the d~vice, pore densities less th~n 10 per square cm may be used.
The thin sheets 12 and 14 may be joined at their respective edges to form ~dge 16 in a variety of waysO Various heat and impulse sealers can be used with variations in temperatures, freguency, and times allowing for substantial flexibility depending upon ~he particular polymer. Various one part and two-part compatible adhesive bonding systems such as EASTMAN 91oR, EPON 828 and 3M CONTACT CEMENT could also be used. In addition, some materials are suitable for bonding without using conventional bonding methods~
For example, vinylidene chloride may be sealed to itself while in the so called "supercooled" state to form a strong bond without conventional dielec~ric heat or adhesive methods.
Osmotic pre~sures generated in cavity 18 sbviously will be si~nificantly less than the burst strength of the semipermesble membranes. For example, the pressure generated by the macromolecule will be on the order of less than 0.34 atmosphere l5 pounds per sguare inch), whil~, for example, the burst strength of ~inylidene chloride 1 mil thick is 30 pounds per s~uare inch.
The following specific examples of delivery systems, in accordance with the invention, are set forth as illustrative only, and should not in any way limit the scope and purpose of the present invention.
A delivery sy~tem for the drug phenytoin, is constructed by forming a sheath made from planar sheets of polycarbonate membrane, with pore size of 0.015 micro~eters, porosity 12 x 108f 2 and thickness 6 micrometers~ The polycarbonate membrane is heated to 220 degrees Centrigrade, and molded by vacuum or pressure ~o a ~pherical cap of 6.0 mm dia~eter with radius of curvature~ 6~ 4 mm. A 1/2 mm w.ide planar circumferential cuff i~ left about each empty spherical cap. Then, 25 ~1~ of phenytoin, alc~ng with 100 ~g of albumin are placed into one cap after which ~he opposing cap is utilized as a cover and the circumfsrential cllf of lf2 m~ is sealed ltogether at 23D-275 deyrees Centigra~e.
This crea'ces an enYelope o~ potential volume ~ 2 mm3,, Placed in the fluid environment of use, the 10 delivery sys~em will f ill to its normal volume .
Figure 3 is a plot of the delivery rate of syste~s according to the invention comparing the delivery rate of a system oontaining ph0nytoin albumin complex with the delivery rate s~f a system containing phenytoin alone . In the f irst h~lf-hour the system utilizir~g the drug phenytoi.n-albumin comp~ex shows that ID"74~ of i1 s drug content by wei~ht will have been expended and afte olle hour a to~al of 1. 7% will have beQn experlded, and so on fo3r the followin~ intervals~ 2 hrs, 3.4%; 4 hrs~
20 5.4%, 10 1/2 hours~ 12%; 24 hrs, 20.2%~ 33 1~,2 hrs, 27.2%.
By contrast, ~n identical device containing only phenytoin without albumin will d~`l iver at the idell'cieal time intervals as noted abc~ve, the following percesltages of th~ initial amount of drug placed in the device. 1/2 hr~ 1.47~; 1 hr, 2.97~; 2 hrs, 5i7%; 4 hrs, 9.6~; 10 1/2 hr~? 22.4~6; 24 hrs, 38%; 33 1~2 hrs, 47.2%
The osmotic d~vice accc>rding to the inv~ntion will now be described in its embodimen~ a~ a lens~ Again 30 referrin~ to Fiç~ures 1 and 2, when osmo~ic device 10 is employed as a lenE;, thin sheets 12 and 14, are made o transparent material and are bc3und along their respeetive edges to form sheal:h 19 which def ines cavity 18 for retaining a b~dy of f luid . In accordanee with this embo~3ime~t c>f the invention, the body of :Eluid comprise~
the primary lens m~dium. The primary func~ion of the tranSparent th:ln sheets 12 and 14 is not te) c:onstitute part of ~he le~ ns medium~ but is to re~ain ~he body o~E

fluicl in a shape that will enable it to serve as the primary lens medium. As will be apparent hereafter, the lens according to the invention, is intended to be used in a fluid environment with sufficient fluid present to enable the lens to operate as intended. The body of fluid retained by the sheath formed by the thin trans-parent sheets 12 and 14 will not necesszrily be present when the lens is not being used in its intended environment.
As in the delivery system described above sheets, 12 and 14 are provided with a plurality of pores in order to be semipermeable and permit the passa~e of fluid therethrough. The semipermeable thin transæarent sheet 12 and 14, when joined to orm edge 16 result in a semipermeable sheath.
In accordance with the present invention the lens utilizes the principle of osmotic flow which results rom a difference in molecular concentration being present across a semipermeable membrane.
According to this embodiment of the invention, cavity 18 will contain at least one macromolecule which will go into solution with the fluid in cavity 18 and the macromolecule along with the fluid in cavity 18 will form the body of fluid which conlstitutes the lens medium. The presence of the macromolecule in solution in the body oE
fluid in cavity 18 results in a molecular concentration gradient being set up between the body of fluid in cavity 1~ and the fluid environment in which the lens is used.
As described in connection with the embodiment of the delivery system, ~his molecular concentration gradient results in a net flow of fluid from the fluid environment through semipermeable sheath 19 into cavity 18, because the fluid inside the semipermeable shea~h has a higher osmotic pressure than the fluid outside the semipermeable sheath due to the presenc~ of the macromolecul~ in cavity 18.
To assure that this concentration gradient is maintained, the macromolecule and semipermeable sheath are selected such that the macromolecule will not flow 6~

lB
out of cavity lB through the semipermeable sheath, yet the semipermeable membxane will permit the flow of fluid from the environment in which the lens is used into cavity 18. Because the macromolecule eanno~ leave cavity 18, the molecular concentration inside cavity 18 and the molecular concentration outside cavity 1~ will never e~ualize. Since, normally, osmotic ~low will continue until the molecular concentrations are equali~-ed, there is always a tendency for the surrounding fluid ~o flow through the semipermeable sheath. The ~ize ~f cavity 18, however, is determined by sh~ath 19, and ~he tens.ile strel~gth of sheath 19 is ~tronger than the osmotic pressure exerted due to the molecular concentration diferenees~ Cavity 18 thus always remain~ ull when disposed in its intended enviro~m~nt.
When osmotic device 10 is utilized in connec-tion wi'ch an ocular lens, the surrounding fluid envirc~n-ment will ~enerally consist of 1achrymal fluid and cavity 18 will f i11 with such lachrymal f loid. As a intraocular 20 lens, aqueous humor will surround the lens and ~e at an e~uilibrium with the inl:r~lenticular fluid. As an intrac~rneal lens, the int:ers'citial f 1uid of ~he cornea will CQmprise ~he fluid wi~:hin cavi~y 18.
In thi~ embodiment of th~ invention, the macromo~ecule, should generally be photos~able and inert to assure proper performance of the lens. The macromol-ecule may be selected f rom any class Df compounds with molecular weight and configuration sufficiently large to be excluded passage by the desired pore size~ ~enerally 30 sui'cable are the dextrans, amylopectins ~hydroxyethyl-starch), polyvinylpyrrolidone, polyethylene ylycol and v~rious other soluble polymers, proteins and/or physiolog-ically active agen'cs.
Osmotic device 10 may serve the dual function of a lens as well as a delivery system due to the princi-ple that, as discussed above, the osm~tic flow which -results ~rom molecular concentration differences is ~2~P6~4~

independent of each molecule involved. Thus, a lens according to this aspect of the invention can be utilized for the delivery of physiolo~ical agents by incorpnrating ~uch agents within cavity 18 and selecting the active agent such that it has a molecule size sufficiently small to pass through the semipermeable sheath. Prefexably, a second macromolecule would be tag~ed with the physiolog-ical agent and the macromolecule ~elerted such that it would be larger 'chan 'che pores of the semipermeable 10 sheath, yet it would decay over a period of time thereby allowing tl e actLve agent to slowly disperse from the semipermeable sheath. All the while, ho~ever, the first macrom~lecule, which is larger than ~che pore size of the semipermeable sheath, i5 confined within cavity 18.
Because of the osmotiG pressure generated by the f irst macromolecule, as soon as an~ active agent leaves the cavity, the ~urrounding flu.id will still enter cavity 18 to maintain the l~ns configuration.
The active agents suitable for use in connec-tion with the lens of the present invention include forexample: oxygen, preferentially bound to fluorocarbons;
salicylates, catechols~ Aalogens, barbiturates or other compounds complexed to a mac:romolecule such as polyethyl-ene ~lycols; antibiotics such as chloramphenicol, ~ulfa or other medications complexed with a macromolecule such as polyvinylpyrrolidone; antihi~tamines, quinine, pro-caine or other compounds complexed to a macromolecule such as sodium carboxymethylcellulose; ~alicylates complexed to the antibiotics oxytetracycline or tetracy-30 cline or o~cher compounds com}?lexed ~co a macromolecule~uch as salicylates or other macromolecules could be utilized such as caffeine or albumin. lSee generally R min~zton '8 Pharmaceutical_~ciences, and Physical Phy~, cited above ) .
The delivery rate of active agent and/or complexing molecule is determined ~s previously discussed in connection with the osmotic device as employed in a delivery ~ystem. .

6 ~U ~9 When eoncerned with ocular lenses, the m~mbrane thickness will generally range from 5-10 micrometers, again depending upon the ma~erial used and the desired configuration and concentration gradient intended to be utilized, The ~heet material for sheath 19 in the lens emb~diment could be selected from among the ~ame mater-ials listed above relative to the use of the osmotic device as ~ delivery system and the ~ame processes as described above may be use~ lto create the pores in the transparent sheets and to join the respective edges to form edge 16. A180~ the pore si2e will preferably be the sama as previously discus~ed.
The refractive index of the lens will be determined by compo~ition and concentration of the body of liquid formed in cavity 18. For example, dilute solu~ Dns of dextran ~average molecu~ar weight 75 000) and amylt~pectin have a refractive index imilar to that of plain water or ~aline s~lution, 1. 336 . tAmylopectin average molecular weight, 545 167)~ A 1796 solution of 20 amylopectin has a refractive index o 1.432.
Turning now to ~:igures 4 and 5, there is 4hown lense~ 20~ 30 in accordance with ~he invention, in the fonn of ~ contacc lers. I.ens 20 t~f Figure 4 is made Gf a thin tr~nsparent sheet 21 o semipermeable material as previou~ly described~ While the lens ~f Figure 4 is ~n ocular conDcaet lens having a generally cir ular ct~nfigur-a~ion, the prineiples of the invention are e~ually applicable to lenses of other ~hapes or other uses.
Furthermore, while the lenses shown in Figures 3 and 4 are hyperopic con~act lenses/ ~he present invention is likelwise suitable for myopic contact lenses. As ~he anterior surface is regular and independent of the posterior curv2lture, it will neutralize corneal astigma-tism and/or irregularity.
Lens 20 includes scaffolding 29 on the rear ~urface of the semipermeable sheet 21. The scaEfolding 29 serves to give additional support ~o sheet ~1.

Scaffolding 29 comprises polymethylmethacrylate, polypro pylene, cellulose acetate butyrate, hydroxymekhylmetha-crylat~ or other rigid, semirigid or soft polymer strands Scafolding 29, as shown in Figure 4, i5 ~ish net in configuration; however, it may be a variety of designs such as concentric rings connected by radial spokes, arcuate cro~sin~ elements, radial strands, a mesh of criss-crossin~ meridional fibers~ etc. In addition, while scaffolding 29 is shown in connection with contact lens 20 of Figure 4 and 5, it could also be used in connection with other lenses, in accordance with the invention, such ~s th~ lens shown in Figures 1 and 2.
In addition, as was the ca~e with the formation of the semipermable sheath, the scaffolding may be joined to the lens by known prior art method~ such as by heat impulse sealing, adhesives, or during the manufacturin~ of the semipermeable sheath.
Turnin~ now to ~.igure 5, l~ns 30 is shown, in place, on the cornea of the wearer~ Figure 5 shows a human eye including a cornea 41, iris 42, eye lens 43, anterior chamber 44, posterior chamber 47 and posterior capsule 4g. Thin transparent sheet 31 rests on cornea 41 and retain~ a body of fluid 33 which functions as the primary lens medium. A~ described in connection with the embodiment of Figures 1 and 2, the body of fluid 33 contains a macromol0cule and has a higher concentration than the surrounding ocular fluid, primarily lachrymal fluids. ~ecause the body is of higher concentration than the surrounding body fluids, the cavity deined by the thin, transparent sheet 31 and the cornea 41 will remain filled with fluid. Instead of being provided with ~caffolding for added support, contact lens 30 includes a larger diameter outer portion 35 made of svft permeable material which serves as a lens carrier to support contact lens 30. Alternatively, the lenses, according to the invention~ could utilize both scaffolding and a lens carrier if desired.

Figure 6 shows an intraocular lens 50 in ~ccordanee with the invention partially inserted in the ey~ cavityr Lens 50 is provided with haptic support struts which serve to anchor the lens to the eye cavity.
According to the method of this embodiment of the inven-tic)n, because lens 50 is fl.exible and can be inserted in the eye in a dehydrated state, the lens may be folded or rolled to a size smaller than its hydra~ed size. This permits the use of a small incision as compared with prior ar~ methods of insertion and results in lessened trauma to the patient. Once the dehydrated lens is inserted in the eye, it can be unolded or unrolled and then permitted to hydrate in order to function as a lens.
The following speciflc examples o~ lenses consl:ructed in accordance with the :invention are set forth a~ illustrative only, and should not in any way limit the scope and purpose of the present invPntion.
Example I
A contact lens at:cording to this embodiment of the invention may be constructe~ for a moderately far-sighted patient aiEter a S~ataract extraction~ a moderately extr~me example of need for hyperopic or ~+N correction of ~140 00 diopters~ A semipermeable shea~h of p~lyvinyl-idene ehloride is provided which has been exposed to Califorrlium 252 to create ~ pore density of about 10,000 pores per square cm and then etched in potassium per-manganate at 55 degrees Centigrade for a time appropriate to create a pore diameter of 100 Angstroms. ~ refraetive index of 1.366 is arbitra--ily chosen and will require a solution of 20% amylopectin~ A wide and ~enerous optical zone of 7.0 mm i~ selscted. The lens is designa-ted to be f itted to a cornea so that its posterior radius will conform, for example~ with an average 7.8 mm radius of the cornea. Given these parameters, an anterior curvature o~ the lens of 6.0 mm radius will occur and result in an extremely Eavorable thin lens having a central maximulll thickness of the lens of 0~3 mm. The ~Z~6~9 volume of the lens will be 6.19 mm and thus 1.5 mg of amylopectin will create the desired 20% solution and refractive index of 1.366. Th~ periph~ry o the lens can be h~at~sealed at 225-260 degrees Fahrenheit~ If neces-sary, a posterior scaffolding can be constructed of polymethyl~ethacrylate, a silicon polymethylmethacrylate polymer, polypropylerle or hydrogel and joined 'co either posterior and/or anterior polymer films by heat impulse, oompatible adhesive or the manufacturing proc~ss itself when mesh and/or film are iin a precast state.
~ ple II
__.
A concave lens to correc~ high ~yopia, thus ~aining ~inusl' power can bP simtlarly eons~ructed~ For example, a lens correcting relatively extre~e myopia of -10.00 diopters, can b~ construct~d. Assuming a cornea of average radius of 7~8 ~m, choosing a refractive index for th~ lens of 1.366 etlualling the inde~ ascertained for a 20~ solution of amylopet:tin, an~ a large optical zone ~f 7O0 mm dia~eter, the r~squired anterior radius of the lens will be 9~9 mmO Giiven the basic stability and characteri~tics of thls ~type of lens, it can b~ con~
structed with no signifi.cant center point thickness except for the thickness ~f the opposing membranes, thus attaining a maximum v~rtic~l height at Its lateral thickest portion of 0.19 ~. The volume of this l~ns is 4.58 mm and ~hus l.l mg of amylopsctin will be added to the lens cavity~ The osmotic pressure generat~d in the lenses is well below the burst strQngth of 30 pounds per square inch or a 1 mil film of polyvinylidene chloride.
Ex~
A lens for incorporation within the corneal substance (keratophakia) can be simil~rly constructed.
The followin~ conditions are assum~cl: an example o~
aphakic hyperopia~ the ne~d to generat~ a total ocular power ~rom the posterior corneal ~urf~ce of 60 diopter~;
an avera~e n~r~nal anterior corneal radius of 7uB mm ~nd a posterior corneal radius of 6,~ mm~ As an ~xtre~

2~
example, the lens may be made with a dilute solution of macromolecules such that the refractiv0 index approaches ~hat of water and aqueous humor and tears, namely 1.336, less than that cf the cornea itsel (1.376). A large optical zone of diameter of 7.0 mm is chosen and a new anterior csrneal radius of 5.6 mm is necessaryO 'rO
achieve this change in corneal con~ig~ration, a ienti-cule, with an anterior radius o~ 5.35 mm, a posterior radius of 7.55 mm, thus generating a central maximum thickness of 0.4 mm should be fabricated. Obviously, for increasing refractive index, a decreased thickness for arly ~iven diameter of optical zone can be achieved by requiring less of a change in the ante~ior convexity of the cornea. Reduction in corneal convexity, by incorpor-ating minus concave lenses for the correction of myopia, can be similarly accomplished by fashioning such intra-stromal lenticules as desc:ribed for the contac~ lens.
Support sc~ffoldlng can be incorporat~d into the anterior and/or posterior surfacs as needed. The periphery of this par~icular lens may be impulse s~aled after incor-poration of less than one-half mg of dextran ~less than 5~ solution), requiring a peripherally sealed zone of 1/2 to 1 mm for a total 8.0 to 9~0 mm diameter lenticule.
Example IV
An intrac>cular lens may be constructeæ in accordance with the invention. Assuming an average intraocular lens power of 20 diopters, a lens symmetric-ally biconvex, and 33-1/3~ solution of dextran or amylo-pectin with a refractive index of 1.400/ a generous op~ical zone Eor an intraocular lens of 6.0 mm diameter is chosen, thus requiring a radius anteriorly and poster-iorly of 6.4 mm and creating a total thickness at the center maximum of 1.4 mm. The lens will have a volume of 11.92 mm and thus re~uire incorporation of 5.9 mg of dextran or amylop0ctin. This l~ns may be constructed so that it has a 1/2 mm wide circumferen~ial seal which incorporates thin support haptics enabling ~he lens in its dehydrated state to b~ folded or rolled and maneuv-ered into the eye through an incision 3~1/7 to 4 mm long.

~6~

It will be understood that the above description of the present invention is susceptible to various modifica-tions, changes arld adaptations and the same are intended to be comprehended within the meaning and range of equivalents of th0 appended claims.

Claims

CLAIMS -

1. An osmotic device for immersion in a physiological fluid comprising:
a semipermeable sheath defining a fully enclosed cavity and being imperforate except for a plurality of pores for permitting the flow of the physio-logical fluid into said cavity, and at least one macromolecule disposed within said cavity and having a size larger than the pores in said sheath so that said mlacromolecule is prevented from leaving said cavity when said device is immersed in the physiological fluid, such physiological fluid being caused to flow into said cavity through said pores under the influence of osmotic pressure;
wherein said cavity will always contain a molecular concentration greater than the molecular concentration of physiological fluid surrounding said sheath,

2. A system for the controlled delivery of a physiologically active agent to a fluid environment comprising the osmotic device of claim 1, and further including a physiologically active agent complexed to said macromolecule such that said physiologically active agent dissociates from said macromolecule over time, goes into solution with the fluid in said cavity and passes out of said cavity through said pores whereby said physiologically active agent is delivered from said semipermeable sheath exclusively through said plurality of pores.

3. The system of claim 1, wherein said sheath is transparent and said macromolecule is photostable.

4. The system of claim 1, wherein said macromolecule is inert.

5. The system of claim 1, wherein said macromolecule is selected from a group consisting of protein, cellulose, carbohydrate, rubber or high polymer.

6. The system of claim 1, wherein said sheath has a thickness of less than 50 microns.

7. The system of claim 1, wherein the diame-ter of said pores is less than 1,000 Angstroms.

8. The system of claim 1, wherein said sheath has a pore density between 100 and 1010 pores per square cm.

9. An ocular lens system comprising the osmotic device as defined by claim 1, wherein said sheath is transparent and the physiological fluid which flows into said cavity through said pores under the influence of osmotic pressure constitutes an optical lens.

10. A lens comprising a semipermeable transparent sheath having opposite anterior and posterior portions joined at their edge and forming a closed interior space between them-selves;
a body of liquid within said sheath and filling said interior space, said body of liquid consti-tuting an optical lens whose anterior and posterior surfaces are bounded by said anterior and posterior portions of said sheath, respectively, thus defining the anterior and posterior surfaces of the lens; and means in said body of liquid for producing within said interior space a concentration which is greater than the concentration of a liquid medium in association with which the lens is to be used, in conse-quence of which when said lens is in contact with such medium, the interior space will be kept filled with liquid under the influence of osmosis which causes the flow of liquid from the exterior of the sheath to the interior thereof whenever the interior space is less than full thereby maintaining the shape of the lens.

11. The lens of claim 10, wherein said trans-parent sheath has a thickness of less than 50 microns,

12. The lens of claim 10, wherein said body of liquid and said medium in association with which the lens is to be used comprises a physiological solution.

13. The lens of claim 12, wherein said physio-ogical solution comprises a physiological saline solu-tion.

14. The lens of claim 12, wherein said body of liquid further includes a physiologically active agent.

15. The lens of claim 10, wherein said semiper-meable transparent sheath comprises a transparent sheet having a plurality of pores.

16. The lens of claim 15, wherein the diameter of said pores is less than 1, 000 Angstroms.

17. The lens of claim 15, wherein said trans-parent sheet has a pore density between 100 and 1010 pores per square cm.

18. The lens of claim 10, wherein said means for producing within said interior space a concentration which is greater than the concentration of a liquid medium in association with which the lens is to be used comprise. a macromolecule.

19. The lens of claim 10, wherein said pores are sufficiently small to prevent the passage there-through of said macromolecule.

20. The lens of claim 18, wherein said macro-molecule is photostable.

21. The lens of claim 18, wherein said macro-molecule is inert.

22. The lens of claim 18, wherein said macro-molecule is selected from a group consisting of protein, carbohydrate, rubber or high polymer.

23. A contact lens, comprising a concave semipermeable transparent element adapted to seat on a human cornea to form therewith a closed interior space which contains a body of physiological liquid produced by the wearer of the element, said body of liquid consti-tuting an optical lens whose anterior surface is bounded by said element and whose posterior surface is bounded b the cornea of the wearer; and means carried by said element at its interior for producing within said inter-ior space, when the same contains said body of liquid, a concentration which is greater than the concentration of the physiological solution produced by the wearer of the contact lens, in consequence of which when said element is worn on the cornea, said interior space will be kept filled with liquid under the influence of osmosis which causes the flow of liquid from the exterior of said space to the interior thereof whenever said interior space is less than full.

24. The lens of claim 23, wherein said body of liquid further includes a physiologically active agent.

25. The lens of claim 23, wherein said transpar-ent element has a thickness of less than 50 microns.

26. The lens of claim 23, wherein said means for producing within said interior space a concentration which is greater than the concentration of a liquid medium in association with which the lens is to be used comprises a macromolecule.

27. The lens of claim 26, wherein said macro-molecule is photostable.

28. The lens of claim 25, wherein said macro-molecule is inert.

29. The lens of claim 26, wherein said macro-molecule is selected from a group consisting of proteins, carbohydrate, rubber or high polymer.

30. The lens of claim 26, wherein said pores are sufficiently small to prevent the passage there-through of said macromolecule.

31. The lens of claim 23, wherein said semiper-meable transparent element comprises a transparent sheet having a plurality of pores.

32. The lens of claim 31, wherein said transpar-ent sheet has a pore density of between 100 and 1010 pores per square cm.

33. The lens of claim 31, wherein the diameter of said pores is less than 1,000 Angstroms.

34. The lens of claim 33, wherein the diameter of said pores is between 50 and 1,000 Angstroms.