United States Patent
`
`(9)
`
`Theeuweset al.
`
`[54] OSMATIC DISPENSING DEVICE FOR
`RELEASING BENEFICIAL AGENT
`
`Inventors:
`
`Assignee:
`Filed:
`
`Felix Theeuwes, Los Altos, Calif.;
`Takeru Higuchi, Lawrence, Kans.
`
`Alza Corporation, Palo Alto, Calif.
`
`June 5, 1972
`
`[57]
`
`ABSTRACT
`
`[75]
`
`[73]
`
`[22]
`
`[21]
`
`[52]
`
`[51]
`[58]
`
`[56]
`
`Appl. No.:
`
`259,469
`
`U.S. Chote. 128/260, 128/130, 222/389,
`424/15, 424/37
`Int. Chi cccccccseceseeee dceuteevatenes A61m 31/00
`Field of Search........... 128/260, 130, 272, 269,
`128/127-129, 213; 99/77.1; 424/15, 37,
`19-21; 222/386.5, 389; 206/.5
`
`References Cited
`UNITED STATES PATENTS
`4/1912
`Bell... ceecceecseeesseetseeeneees 128/260
`McCIUre 00... eeceeeeeeeeeeeneeeee 128/272
`9/1918
`
`11/1922
`CYPeNius .....eee 128/272
`
`8/1958
`0)Ll 206/.5
`
`11/1960
`Chappazet al... 128/260
`6/1963
`JOrdan .... eects 128/260 X
`8/1964
`Stephensonet al... 424/15
`12/1968
`NESS... ceeeccceeeececeeetseeerenetens 128/260
`
`Johnsonetal.....
`wee 424/37 X&
`4/1971
`
`12/1971
`Higuchi... eee 128/260
`
`1,023,499
`1,279,564
`1,434,531
`2,846,057
`2,962,023
`3,093,831
`3,146,169
`3,416,530
`3,574,820
`3,630,200
`
`{11]
`
`[45]
`
`3,845,770
`Nov. 5, 1974
`
`Primary Examiner-—Richard A. Gaudet
`Assistant Examiner—J. C. McGowan
`Attorney, Agent, or Firm—Paul L. Sabatine; Edward
`L.:Mandell; William H. Benz
`
`A wail surrounding and forming a compartment for
`containing a useful composition of matter and having
`a passageway for dispensing the composition is dis-
`closed. The wall is comprised in at least a part of a
`material permeable to an external fluid. The composi-
`tion is soluble in the fluid and exhibits an osmotic
`pressure gradient against the fluid or the composition
`has limited solubility and is admixed with an osmoti-
`cally effective compoundsoluble in the fluid that ex-
`hibits an osmotic pressure gradient against the fluid. In
`operation, composition is dispensed from the device
`by fluid permeating into the compartment producing a
`solution of the soluble composition or a solution of the
`osmotically effective compound containing the com-
`position, which solution in either operation is released
`through the passageway to the exterior of the device
`at a rate controlled by the permeability of the wall and
`the osmotic pressure gradient across the wall of the
`device.
`.
`
`15 Claims, 8 Drawing Figures
`
`oT
`
`16
`
`12
`
`AUROBINDO EX1017, 1
`
`AUROBINDO EX1017, 1
`
`

`

`PATENTEDNOY 5 1974
`
`SHEET 1 OF 3
`
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`
`FIG.2
`
`FIG.3
`
`AUROBINDO EX1017, 2
`
`AUROBINDO EX1017, 2
`
`
`
`

`

`PATENTEDKOY 5 1974
`
`|
`
`SKEET 20F 3
`
`3,845,770
`
`AUROBINDO EX1017, 3
`
`AUROBINDO EX1017, 3
`
`

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`3,845,770
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`1
`OSMATIC DISPENSING DEVICE FOR RELEASING
`BENEFICIAL AGENT
`
`FIELD OF THE INVENTION
`
`This invention pertains to both a noveland useful de-
`vice for dispensing a useful composition of matter.
`Moreparticularly, the invention relates to a dispensing
`device for the controlled and continuousdispensing of
`a composition over a prolonged period oftime to pro-
`duce a beneficial effect. Specifically, the invention con-
`cerns an osmotic dispenser manufactured with a mini-
`mum number of components and suitable for adminis-
`tering an active agent at a controlled and continuous
`rate to achieve a predetermined useful effect in ani-
`mals, humans and other environments.
`
`2
`a drug release nipple, and in operation when the prod-
`uct compartment is charged with a solution of a prod-
`uct, water in the water compartment moves through
`the semi-permeable membrane into the dye solution
`increasing its volumein the compartmentcausingit to
`expand against the rubber providing the. mechanical
`force necessary to eject the product solution through
`the nipple.It is immediately evident that this device has
`certain adverse features that tend to diminishits practi-
`cal use. For example, the deviceis difficult to construct
`into compartmentsthatare essentially free of leaks plus
`the fabrication demands of a movable material that ne-
`cessitates a rigid outer housing. Another inherent dis-
`advantage which prevented its wide acceptance by the
`medical communityis the requirementthat the product
`be in solution which exhibit a deleterious tendency to
`be released from the device by simple leaching, the use
`ofa solution of the product which use does not permit
`high concentrations of the product to be embodied
`within the device, the demand for an osmotically effec-
`tive solute other than the product, and that many prod-
`ucts on prolongedstorage in solution undergo chemical
`deterioration. The device is further of limited value be-
`cause it must carry its own water which increases the
`size of the device and thusly limits its use to a few envi-
`ronments. Anotherprior art attempt to provide a prod-
`uct dispensing device is disclosed in U.S. Pat. No.
`3,604,417. The device disclosed in this patentis similar
`to the earlier prior art devices, and its design requires
`a semi-permeable membrane, a separate osmotically
`effective solute, a solution of the product and addition-
`ally the presence of a movable piston. The movable pis-
`ton severly restricts the shape of the device, and this
`device, as with the above mentioned device, has not en-
`joyed wide acceptance because of construction prob-
`lems and the inherent features that limit the use of the
`device.
`In copending patent applications U.S. Ser. No.
`106,131 filed on Jan. 13, 1971 and U.S. Ser. No.
`106,161, filed on Jan. 13, 1971, with both applications
`assigned to the same assigneeofthe application, there
`is disclosed novel and useful osmotic dispenser devices
`that represent an improvementto the art. While these
`devices have made a valuable contribution to the art,
`they are designed with moving parts that tend. to com-
`plicate their manufacture and they require, in addition
`to the product, the constant presence of an osmotically
`effective solute that exhibits an osmotic pressure gradi-
`ent against water. This latter feature generally in-
`creases the size of the device and concommitantly re-
`stricts its use to fewer environments.
`
`OBJECTS OF THE INVENTION
`Accordingly, it is an immediate object of this inven-
`tion to provide a novel dispensing device for the. dis-
`pensing of a composition of matter to produce a benefi-
`cial effect, which device overcomesthe aforesaid dis-
`advantages associated with the prior art devices.
`Still another object of the invention is to-provide a
`novel dispensing device for dispensing a composition of
`matter at a controlled rate for a prolonged period of
`time.
`.
`Yetstill another object of this invention is to provide
`a novel and useful dispensing device that is simple in
`construction, designed with a minimum number.of
`parts, easy to use, and in operation exhibits all the prac-
`tical and useful benefits obtained by the controlled,
`
`AUROBINDO EX1017, 5
`
`BACKGROUNDOF THE INVENTION
`Dispensing systems for the delivery of compositions
`of matter are well known to the prior art. These systems
`generally deliver their composition by diffusion, for ex-
`ample, from an enclosed capsule or by diffusion from
`a multi-structured device having a wall formed of a
`known polymer permeable to the composition into a
`selected environment. However, there is a large cate-
`gory of compositions that cannot be delivered by the
`prior art delivery systems. because of at least one fea-
`ture inherent in these devices which adversely affects
`their rate of release from. the system or substantially
`prevents the release of the composition from the sys-
`tem. For example, many compositions cannot be deliv-
`ered from a diffusion controlled delivery system be-
`cause their permeation rate through the rate control-
`ling material comprising the system is too small to pro-
`duce a useful effect, or in many instances the composi-
`tion molecules are too big and will not diffuse through *
`the rate controlling material forming the device. Also,
`there is an additional class of useful products that can-
`not besatisfactorily delivered by diffusion devices be-
`cause of a particular chemical characteristic of the
`product. This additional class includes salts that be-
`cause of their ionic character will not diffuse through
`most polymers and polymeric like materials and unsta-
`ble polar compounds that cannot be formulated into a
`satisfactory composition suitable for storage and deliv-
`ery from a prior art device. Prior art diffusion systems
`encompassed within the above discussion are typically
`represented by U.S. Pat. No. 3,279,996, and thelike.
`
`20
`
`25
`
`30
`
`4(°
`
`45
`
`50
`
`55
`
`60
`
`The prior art attempted to overcome the above men-
`tioned adverse features by proposing devices seemingly
`capable ofreleasing.a solution containing a product at
`a relatively constant rate. One such deviceis disclosed
`in ‘Austral. J. Exp. Biol.,”” Vol. 33; pages 415 to 420,
`1955. This device consists of three compartments con-
`fined in a specifically constructed housing and a clamp
`to hold a semi-permeable membrane. The driving force
`of the device depends on the continual presence of a
`solution of an osmotically effective red dye solute that
`exhibits an osmotic pressure gradient against water.
`The red dye is contained in a partially collapsed rubber
`compartment and it is separated. from a second com-
`partment containing water by a semi-permeable mem-
`brane. Thepartially collapsed bag is housedin a glass
`ampoule, along with a product compartment defined
`by the space between the bag and one endofthe glass
`ampoule. The distant end of the ampoule defines a
`water compartment. The ampoule alsois provided with
`
`AUROBINDO EX1017, 5
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`3,845,770
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`4
`solution of the osmotic compound containing the latter
`composition, which solution in either instance is dis-
`pensed from the device by a constant influx of fluid
`from the environment and wherein theinflux is gener-
`ated by the continuousdissolution of the composition
`or the osmotically effective compound in the fluid dif-
`fusing at a controlled rate through the wall under the
`osmotic pressure gradient across the wall into the com-
`partment. The device can in operation dispense a com-
`position at a zero orderrate of release for a prolonged
`period of time by maintaining the rate of dissolution of
`the composition, or the osmotic compoundin the fluid
`constant. In the device, thelatter is accomplished when
`the dissolution rate is larger than the rate of release of
`the composition or the osmotic compoundin the fluid
`present in the passagewayto the exterior of the device.
`
`3
`continuous, long-term administration of various com-
`positions of matter, that is, active agents to animals,
`avians, humans and into other receptive environments.
`
`A further objectofthis inventionis to provide a novel
`dispensing device that can administer a complete phar-
`maceutical dosage regimen fora particular time period,
`the use of which requires intervention only for initia-
`tion and termination of the regimen.
`Another object of this invention is to provide an im-
`proved dispensing device which will permit high con-
`centration of an active agent to be contained therein,
`and which high concentrationsof the agent will not ex-
`hibit the tendency to be leached from the device nor
`have its potency decreased by chemical breakdowns.
`Yetstill a further object of the inventionis to provide
`a novel product dispensing device that contains a prod-
`uct which product can be used as an osmotically effec-
`tive solute to exhibit an osmotic pressure gradient
`against an external fluid.
`Yet a further object of the invention is to provide a
`product dispensing device that contains a productin a
`form suitable for storage thereby giving the device an
`improved shelflife.
`Yet another immediate object of this invention is to
`provide adispensing device for the administration of
`locally acting or systematically acting drugs to produce
`a physiologic or pharmacologic effect and which device
`can release the drug at a rate that does not vary with
`time.
`Still yet another object of the invention is to provide
`a device containing drugs in various physicochemical
`forms such asesters, salts and the like that can be heat
`sterilized by conventional techniques.-
`Yet another important object of the invention is to
`provide a device for dispensing an active agent which
`device can have avariety of release rates ranging from
`very low to very high by using polymeric wall forming
`materials in combination with the active agent or a mix-
`ture of an active agent and another osmotically effec-
`tive compound.
`Yet still another object of the inventionis to provide
`a novel and useful erodible or biodegradable device
`that erodes or degrades after the device has released
`the active agent.
`Other objects, features, and advantages of the inven-
`tion will be apparent to thoseskilled in the art from the
`detailed description of this specification, taken in con-
`junction with the drawings and the accompanying
`claims.
`
`SUMMARYOF THE INVENTION
`
`The invention concerns a device comprised of a wall
`surrounding a compartment as a meansfor containing
`a useful composition of matter such as a drug, a benefi-
`cial product or the like, and having a passageway com-
`municating with the compartment and the exterior of
`the device for releasing the composition from the com-
`partment. Thewall of the device is comprised in at least
`a part of a material permeable to an externalfluid com-
`mon to the environment of use. Composition is dis-
`pensed from the device by the externalfluid diffusing
`through the wall into the compartmentto dissolve the
`composition or to dissolve an osmotically effective
`compound admixed with a composition having limited
`solubility, producing thereby an essentially saturated
`solution of the composition or an essentially saturated
`
`0
`
`20
`
`30
`
`50
`
`35
`
`65
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`In the drawings, which are not drawn to scale, but
`rather areset forth to illustrate various embodiments of
`the invention, the drawings are as follows:
`FIG. 1 is an illustration of a delivery device of the in-
`vention with a portion of the wall removedto illustrate
`the general structure of the device.
`FIG. 2 is a perspective, top view of a dispensing de-
`vice of the inventionillustrating as one embodiment of
`the invention a device manufactured as an ocular drug
`delivery device.
`;
`FIG. 3 is an enlarged cross-sectional view of the ocu-
`lar drug delivery device of FIG. 2 through 3—3 depict-
`ing two walls with their interior peripheral surfaces in
`intimate contact with the surfaces of a wall positioned
`between the two walls.
`FIG. 4 is an exploded view illustrating three walls
`prior to their union wherein they act in concert to form
`a novel ocular drug delivery device.
`FIG. 5 is a partly diagrammatic, front view of a
`humaneye illustrating an ocular drug delivery device
`of this invention in an operative positionafter its inser-
`tion into the eye.
`FIG. 6 is a view partly in vertical section and partly
`diagrammatic of an eyeball and the upper and lower
`eyelids associated therewith showing the novel ocular
`product dispensing device of this invention in product
`administration operative position.
`FIG.7 is a frontal, fragmentary view of a uterine cav-
`ity showing a product releasing intrauterine device
`manufactured in accordance with the invention and po-
`sitioned in a uterine cavity; and,
`FIG. 8 is still another embodimentof the invention
`illustrating a side, fragmentary view of an anal osmotic
`drug delivery device for releasing a drug in a body cav-
`ity.
`,
`In the drawings and specification,like parts in related
`figures are identified by like numbers. The terms ap-
`pearing earlier in the specification and in the descrip-
`tion of the drawings, as well as embodiments thereof,
`are further described elsewhere in the disclosure.
`
`DETAILED DESCRIPTION OF THE DRAWINGS
`Turning now to the drawings in detail, which are ex-
`amplesof various delivery devicesof the invention, and
`which examplesare not to be construed as limiting, one
`embodimentof a novel osmotic delivery device is indi-
`cated in FIG. 1 by the number 10. Delivery device 10
`is comprised of a body portion 11 and a neck 12 suit-
`
`AUROBINDO EX1017, 6
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`AUROBINDO EX1017, 6
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`3,845,770
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`5
`ably joined to body 11. Device 10 is shown in open sec-
`tion 13 and device 10 is comprised of a wall 14 sur-
`rounding a compartment 15. Compartment 15 is a
`meansfor containing a composition, thatis,it is a prod-
`uct compartment, and it can contain a product, or a
`mixture of products such as a drug or other active
`agent, not shown in FIG. 1. Neck 12 of device.10 in this
`embodimentis extended from body 11 andit is formed
`with a passageway 16 that communicates with chamber
`15 and the exterior of the device through opening 17
`at the end of neck 12. Neck 12 can-be optionally inte-
`grally formed with body I, or it can be separately
`manufactured and then joined to body 11 by conven-
`tional techniques such as adhesivesealing, heat joining,
`laser sealing, and thelike.
`Wall 14 of delivery device 10 is comprised in total or
`in at least a part of a semi-permeable membranethat
`possesses permeability to an external fluid while simul-
`taneously being essentially impermeable to a product
`housed in compartment 15, That is, body 11 formed of
`wall 14 can be of unit construction, or composite con-
`struction with asection of a semi-permeable membrane
`either formed integral in wall 14, or optionally lined or
`laminated to wall 14, Wall 14 can be formedof a semi-
`permeable material that has uniform properties across
`all its dimensions,thatis, it is substantially imperforate
`or substantially homogenous, or wall 14 can be formed
`of a material that is microporous, that is, a material
`having micropores or microholes, or it can be a semi-
`permeable material possessing both of these properties
`while remaining essentially impermeable to a product
`present.in compartment 15. In operation in one aspect
`of the invention, when wall 14 is comprised of a mate-
`rial that is substantially imperforate, molecules of the
`externalfluid dissolve in and diffuse through wall 14 by
`the process of diffusion into compartment 15. When
`wall 14 is made from a microporous material, mole-
`cules of external fluid migrate and diffuse into the mi-
`cropores, as by diffusion, then into chamber 15. When
`wall 14 is made from semi-permeable material having
`both of these properties, external fluid enters the cham-
`ber by a concurrent operation of each of these mecha-
`nisms, thatis, by diffusion through wall 14 and by diffu-
`sion through the pores of wall 14. Wall 14 is formed of
`synthetic or naturally occurring semipermeable materi-
`als and a detailed description of these materials appears
`later in this specification.
`In FIG, 2 there is seen another delivery device 10
`manufactured according to the and mannerofthe in-
`vention, Product and device 10 in this embodimentis
`an ocular drug delivery device, of bean shape, and it is
`illustrated in FIG. 2 in top perspective view. Ocular
`drug delivery device 106 comprised of a wall 14 formed
`of a material that is permeable to an externalfluid but
`substantially impermeable to a drug, not seen in FIG.
`2 that is housed in device 10. Wall 14 carries on. its
`inner surface an inner positioned wall.19 formed with
`a passageway 16, schematically illustrated by dashed
`lines, which wall.19 is extended around the perimeter
`of wall 14 to engage it in sealed relation with another
`wall, not shown in FIG. 2 and positioned distant from
`wall 14. The distant wall can be of the same construc-
`tion as wall 14 or it can be formed of a material that is
`optionally permeable to an externalfluid and imperme-
`able to a drug to form a composite ocular drug delivery
`device.
`
`6
`Referring to FIG. 3, ocular drug delivery device 10
`is seen in cross-section through 3—3of FIG. 2.:Ocular
`drug delivery device 10 of FIG. 3 is comprised ofa first
`wall 14 and a third wall 18 distant from first wall 14.
`Wall 14 and wall 18 bear on their inner surface a sec-
`ond wall 19 that extends around the outer perimeter of
`wall 14 and wall 18 to form a closed drug compartment
`15. Drug compartment 15 is comprised of a composi-
`tion that is drug 20 or a mixture of drugs or thelike. A
`passageway, not seen in FIG. 3, communicates with
`drug chamber 15 and the exterior of the device 10 for
`the release of drug 20. Wall 14 and wall 18 can be the
`same or they can be different and at least one of the
`walls, 14 or 18, or both of the walls, is comprised of a.
`semi-permeable material permeable to the passage of
`external fluid 21, for example, tear fluid in the eye as
`by diffusion, or at least one of the walls, 14 or 18,
`is
`comprised of a microporous material into which tear
`fluid can permeate to subsequently enter chamber 15,
`as by diffusion. While at least one of wall 14 or wall 18
`is permeable to tear fluid 21, bothof the walls are es-
`sentially impermeable to the passage of drug 20. Wall
`19 of device 10 is formed ofa non-allergenic, biologi-
`cally inert, insoluble in tear fluid material suitable for
`joining wall 14 and wall 18 together to form an essen-
`tially closed compartment 15 as defined by the inner
`surfaces of walls 14, 18 and 19. Device 10 when made
`from a material that is insoluble in tear fluid is removed
`from the eye after it completes its drug release program
`and discarded, or, device 10 can be made from a bioe-
`rodible material that bioerodes in situ to harmless end
`products after the device has completed its predeter-
`mined drug release program. The walls,.14, 18 and 19
`of device 10 of the invention are formed of a material
`that can. be rigid, semi-rigid, semi-flexible, flexible .or
`the like, and for the users comfort in contact with skin,
`in body cavities, or in the eye it is preferably a flexible
`material.
`In FIG. 4 there is illustrated the ocular drug delivery
`device 10 of FIGS. 2 and 3 in expanded view just prior
`to the joining of the parts into a composite article of
`manufacture. In device 10, the parts act in concert as
`an ocular drug delivery device to effectively meter a
`drug to the eye and to its surrounding tissues at a con-
`trolled and continuous rate for a prolonged period of
`time for the managementof health and disease. Ocular
`drug delivery device 10 is comprised of a wall 14,a dis-
`tant wall 18 and an inner wall for sealingly joining the
`inner perimeterof wall 14 to wall 19 and wall! 18.to wall
`14 into sealed relation to form a drug compartmentde-
`fined by the inner surface of the walls for containing a
`drug not shown in FIG. 4. Wall 19 has a passageway 16
`that extends through wall 19 and endsat orifice 17 to
`permit the passage of a drug from the compartmentto
`the exterior of the device. Ocular drug device 19 can
`also have passageway 16 through wall 14 or wall 18 in
`lieu of the passageway through wall 19. Also, the de-
`vice can be constructed with one or more passageways
`that are the functional equivalent in an operative em-
`bodimentof a single passageway. Passageway 16 can. be
`of any geometric shape, for example, round, triangular,
`square, elliptical, and. the like..Drug 20 as ‘originally
`contained in device 10 is in solid form, usually a tablet,
`film, in films. mixed with a binder, granules, powdered,
`a solid suspension, particles in liquid, liquid emulsions,
`containing solids, solids in solids and the like, and it can
`be geometric pieces of different shapes such as square,
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`AUROBINDO EX1017, 7
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`3,845,770
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`7
`oval, round, rectangular and thelike. Drug 20 is soluble
`in tear fluid, which is substantially an aqueous medium,
`that is water, and product 20 exhibits an osmotic pres-
`sure gradient against external tear fluid 21. The os-
`motic pressure gradient generally is dependent on the
`solubility of the product or solute in the fluid and the
`concentration difference across the wall. This osmotic
`pressure gradient between drug in the compartment
`and the external fluid will cause water to permeate
`through the wall
`into the compartment producing a
`dissolution and solution of the drug along with an ac-
`companying hydrostatic pressure. In operation, drug 20
`is released through passageway 16 by external fluid
`permeating through semi-permeable walls 14 or 18 or
`both into compartment 15 producing a solution of the
`drug which is released from the device at a rate corre-
`sponding to the rate controlled by the permeability of
`the semi-permeable membraneto the fluid and the os-
`motic pressure gradient between the drug in the com-
`partment and the exterior fluid which combine to force
`drug from the device.
`Referring to FIG. § there is diagrammatically illus-
`trated an ocular drug delivery device 10 positioned in
`immediate contact with an eyeball 29 for administering
`a drug to eye 29 at a metered dosage rate. In FIG. 5,
`eye 29 is comprised of an upper eyelid 30 with eye-
`lashes 36 at the edge of eyelid 30 and a lower eyelid 31
`with eyelashes 32 at the edge of eyelid 31. Eye 29 ana-
`tomically is comprised of an eyeball 33 covered for the
`greater part of its posterior area by a sclera 34 and at
`its central area by a cornea 35. Eyelids 30 and 31 are
`lined with an epithelial membrane or palpebral con-
`junctiva, not shown, and sclera 34is lined with a bulbar
`conjunctiva which covers the exposed surface of eye-
`ball 33. Cornea 35 is covered with a transparent epithe-
`lial membrane, not shown inthis figure. The portion of
`the palpebral conjunctiva which lines upper eyelid 30
`and the underlying portion of the bulbur conjunctiva
`defines an upper cul-de-sac, not shownin FIG. 5, while
`that portion of the palpebral conjunctiva which lines
`lower eyelid 31 and the underlying portion of the bul-
`bar conjunctiva defines a lower cul-de-sac, also not
`seen in FIG. 5. The novel osmotic drug delivery device
`10 ofthis invention is designed for insertion in the cul-
`de-sac of the conjunctiva between sclera 34 of eyeball
`33 and upper eyelid 30, or device 10 as seen in broken
`continuous lines is adapted for positioning in the cul-
`de-sac of the conjunctiva between the sclera 34 of eye-
`ball 33 andlower eyelid 31, generally to be held in drug
`administration position by the natural pressure of the
`respective eyelid.
`Turning to FIG. 6, which is considered in coopera-
`tion with FIG. 5, there is seen a horizontal section
`through a human eye 29illustrating an osmotic ocular
`drug delivery device 10'in drug administration position.
`Eye 29 is generically comprised of upper eyelid 30 and
`lower eyelid 31 with their respective eyelashes 36 and
`32. Eye 29 is further comprised of eyeball 33, cornea
`35 and sclera 34. An upper cul-de-sac 37 and a lower
`cul-de-sac 38 are defined by a conjunctiva 39. Ocular
`drug delivery device 10 is positioned in lower cul-de-
`sac 38 to continuously dispense a metered amount of
`a drug or a combination of drugs from the device to the
`eye andits surrounding tissues over a prolonged period
`of time. In medical operation, after drug leaves the ocu-
`lar drug delivery device, it is transported to the eye and
`its surrounding tissues by physiological processes such
`
`20
`
`30
`
`35
`
`4(a
`
`50
`
`60
`
`8
`as the flow oftear liquid, blinking action of the eyelids,
`and thelike.
`In FIG. 7 there is graphically depicted another prod-
`uct dispensing device 10 fashioned as an intrauterine
`contraceptive antifertility delivery device prepared ac-
`cordingto the spirit of the invention. Device 10,in this
`embodiment,
`is of letter ‘‘H” configuration and it
`is
`adapted to be located within a uterine cavity and it
`contacts the sides 23 as well as the fundus uteri 24 of
`uterus 25. A thread 26is attached to the trailing end 27
`of device 10 for manually removing it from uterus 25,
`Device 10 is comprised of a wall formed of a semi-
`permeable membranesurrounding a product compart-
`ment 15. A passageway 16 serves as a conduit for the
`movementof drug 20 from compartment 15 into uterus
`23. Compartment 15 is comprised of an antifertility
`agent 20 that may besoluble in uterine fluid and exhib-
`its an osmotic pressure gradient against the fluid, or
`agent 20 can havelimited solubility such as slightly sol-
`uble or moderately soluble in uterine fluid and have
`mixed therewith either homogenously or heteroge-
`nously, an osmotically effective solute that is soluble in
`uterine fluid and exhibits an osmotic pressure gradient
`against external uterine fluid. Wall 14 is formed of a
`semipermeable material that lets uterine fluid permeate
`into chamber 15 at a rate controlled by the permeabil-
`ity of the material. In operation, intra-uterine device 10
`in one embodiment
`is comprised of semipermeable
`walls and having its compartment charged with a mix-
`ture comprised of the antifertility agent. progesterone
`that has limited solubility in an aqueous medium and an
`aqueous soluble, osmotically effective solute that ex-
`hibits an osmotic pressure gradient against the aqueous
`medium, thatis uterine fluid, which device 10 is posi-
`tioned in a uterine cavity for releasing the antifertility
`agent at a zero orderrate of release to the uterine cav-
`ity throughout the major portion of the device’s medi-
`cal history. An insoluble antifertility drug 20 also -can
`be used in a form that is soluble in uterine fluid but
`physiologically inactive until its release from the device
`to the uterine cavity wherein it
`is converted by the
`uterus and its surrounding tissues to a physiologically
`active compound. Whena soluble form of an antifertil-
`ity drug is used, it serves as the osmotic solute eliminat-
`ing the need for an additional solute. Antifertility drug
`is released through passageway 16 in the fluid that per-
`meates through the wall producing the osmotic solute
`containing, in the case of a drug of limited solubility,
`undissolved and some dissolved antifertility agent
`which is released at a rate that correspondsto the rate
`controlled by the permeability of the membraneto the
`fluid and the osmotic attraction to the fluid as ex-
`pressed by the osmotic pressure gradient across the
`wall.
`FIG. 8 illustrates another product delivery device 10
`of the invention. In FIG. 8, delivery device 10 is de-
`signed for administering a drug 20 within a body open-
`ing, the anal canal, not shown. Product delivery device
`10 is comprised of a semipermeablewall 14 shaped like
`an obelisk with a lead end 8 anda tailing end 9. Wall
`14 surrounds a product compartment 15 which serves
`as a reservoir for drug 20. Reservoir 16 is comprised of
`drug 20 in solid form that can be released from device
`10 at a metered rate over a prolonged period of time.
`Wall 14 is suitably formed with a passageway terminat-
`ing in an outlet 17 for releasing drug from device 10.
`Wall 14 can be isotropic, wherein the structure is ho-
`
`AUROBINDO EX1017, 8
`
`AUROBINDO EX1017, 8
`
`

`

`3,845,770
`
`25
`
`30
`
`40
`
`9
`10
`mogenous throughout the cross-section of the wall, or
`ment. A more important advantage of the claimed de-
`wall 14 can be anisotropic wherein the structure is non-
`livery device is that it can be manufactured comprised
`homogenous. In this device, as with the devices dis-
`of a minimum numberof parts, that is, a wall and a
`cussed above, drug is released by the operation of the
`composition of matter.
`device as fully described in the earlier devices.
`The wall forming the device of the invention is a ma-:
`While the above FIGS. 1 through8inclusive areillus-
`terial that is semi-permeable, for example a material
`trative of various product delivery devices that can be
`that is permeable to an externalfluid such as. water and
`made according to the invention, it is to be understood
`the like while essentially impermeable to a selected
`that these delivery devices are not to be construed as
`product or to other compoundsin the device. The ma-
`limiting, as the delivery devices of the invention can
`terial forming the wall can be non-erodible or bioerodi-
`take a wide variety of shapes, sizes and forms for ad-
`ble after a predetermined period of time and in each
`ministering, for example, the drug at controlled rates to
`instance it is semi-permeable to solvent but not to sol-
`different areas of the bodyor to different drug receptor
`ute and is suitable for construction of the osmotic pow-
`sites, or for administering other active agents to other
`ered device. Typical materials for forming the wall in-
`environments. For example, the invention includes pes-
`clude membranes knownto the art as osmosis and re-
`saries, prosthesis, artificial glands, cervical rings, intra-
`verse osmosis membranes such as commercially avail-
`uterine drug delivery devices of cylindrical, bullet, el-
`able unplasticized cellulose acetate, plasticized cellu-
`liptical, circular, bulbous,
`loops, bows, or any other
`lose acetate, reinforced cellulose acetate, cel