GB 2 140 687 A 1
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`SPECIFICATION
`Osmotic Device With Dual Thermodynamic Activity
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`This invention pertains to both a novel and unique delivery system. More particularly, the
`invention relates to an osmotic device comprising a wall formed in at least a part of a semi—permeable
`material that surrounds a compartment comprising: (1) a first osmotic composition comprising a
`beneficial agent, and preferably an osmagent and/or an osmopolyer, said composition in contacting
`arrangement with (2) a second osmotic composition comprising an osmagent and an osmopolymer. A
`passageway through the wall connects the exterior of the osmotic device with the first osmotic
`composition containing the beneficial agent for delivering the first composition from the osmotic
`device. The osmotic device is useful for delivering beneficial agents that because of their solubilities are
`difficult to deliver in a known amount at a controlled rate from an osmotic dispensing system.
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`Background of the invention
`Since the beginning of antiquity, both pharmacy and medicine have sought a delivery system for
`administering a beneficial drug. The first written reference to a dosage ‘form is in the Eber Papyrus,
`written about 1552 B.C. The Eber Papyrus mentions dosage forms such as anal suppositories, vaginal
`pessaries, ointments, oral pill formulations, and other dosage preparations. About 2500 years passed
`without any advance in dosage form development, when the Arab physician Rhazes, 86 5——925 A.D.,
`invented the coated pill. About a century later the Persian Avicenna, 980—1 037 A.D., coated pills with
`gold or silver for increasing patient acceptability and for enhancing the effectiveness of the drug. Also
`around this time, the first tablet was described in Arabian manuscrips written by a|~Zahrawi, 936—
`1009 A.D. The manuscrips described a tablet formed from the hollow impressions in two facing tablet
`molds. Pharmacy and medicine waited about 800 years for the next innovation in dosage forms, when
`in 1883 Mothes invented the capsule for administering drug. The next quantum leap in dosage forms
`came in 1972 with the invention of the osmotic delivery device by inventors Theeuwes and Higuchi as
`disclosed in United States Pat. Nos. 3,845,770 and 3,91 6,899. The osmotic devices disclosed in those
`patents comprise a semi—permeable wall that surrounds a compartment containing a useful agent. The
`wall is permeable to the passage of an external fluid, and it is substantially impermeable to the passage
`of useful agent. There is a passageway through the wall for delivering the useful agent from the
`osmotic device. These devices release useful agent by fluid being imbibed through the semi—permeable
`wall into the compartment at a rate determined by the permeability of the semi—permeable wall and the
`osmotic pressure gradient across the semi—permeable wall to produce an aqueous solution containing
`useful agent that is dispensed through the passageway from the device. These devices are
`extraordinarily effective for delivering a useful agent that is soluble in the fluid and exhibits an osmotic
`pressure gradient across the semi—permeable wall against the external fluid.
`A pioneer advancement in osmotic delivery devices was presented to the dispensing arts by
`inventor Felix Theeuwes in United States—Patent No. 4,1 1 1,202. |n'this patent, the delivery kinetics of
`the osmotic device is enhanced for delivering useful agents that are insoluble to very soluble in the
`fluid, by manufacturing the osmotic device with a useful agent compartment and an osmagent
`compartment separated by a film. The film is movable from a rested to an expanded state. The osmotic
`device delivers agent by fluid being imbibed through the semi—permeable wall into the osmagent
`compartment producing a solution that causes the compartment..t0 increase in volume and act as a
`driving force that is applied against the film. This force urges the film to expand against the useful
`agent compartment and correspondingly diminish the volume of the useful agent compartment,
`whereby useful agent is dispensed through the passageway from the osmotic device. While this device
`operates successfully for its intended use, and while it can deliver numerous useful agents of varying
`solubilities, its use can be limited because of the manufacturing stepsand costs needed for fabricating
`and placing the movable film in the compartment of the osmotic device.
`In United States Patent No. 4,327,725 patentees Richard Cortese and Felix Theeuwes provided
`an osmotic dispensing device for delivering beneficial agents, thatbecause of their solubilities in
`aqueous and biological fluids, are difficult to deliver in meaningful amounts at controlled rates over
`time. The osmotic devices of this patent comprise a semi—permeable wall surroundingra compartment
`containing a beneficial agent that is insoluble to very soluble in aqueous and biological fluids, and an
`expandable hydrogel. In operation the hydrogel expands in the presence of external fluid"-that enters the
`device thereby causing the beneficial agent to be dispensed through the passageway from the device.
`This device operates successfully for its intended use, and it delivers many difficult to deliver beneficial
`agents for their intended purpose. Now it has been observed, its use can be limited because the
`hydrogel lacks a present ability to imbibe sufficient fluid for the maximum se|f—expansion needed for
`urging the beneficial agent from the device.
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`it will be appreciated by those versed in the dispensing art, that if an osmotic device -can be
`provided that exhibits a high level of osmotic activity for delivering a beneficial agent by generating in
`situ an expanding force sufficient for delivering the maximum amount of agent at a controlled rate from
`an osmotic device, such an osmotic device would have a positive value and represent an advancement
`in the dispensing art. Likewise, it will be immediately appreciated by those versed in the dispensing art
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`MYLAN - EXHIBIT 1006 - Pait 2 of 9
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`MYLAN - EXHIBIT 1006 - Part 2 of 9
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`GB 2 140 687 A
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`that if an osmotic device is made available possessing dual thermodynamic osmotic activity for
`delivering increased amounts of a beneficial agent, said osmotic device would find practical application
`in the fields of pharmacy and medicine.
`
`Object of the Invention
`Accordingly, in view of the above presentation, it is an immediate object of this invention to
`provide an osmotic system that represents a further improvement and advancement in the dispensing
`art.
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`Another object of the invention is to provide an osmotic system manufactured in the form of an
`osmotic device for delivering in vivo a beneficial drug that is difficult to deliver and now can be
`delivered by the osmotic device provided by this invention in therapeutically effective amounts over
`time.
`'
`Another object of the invention is to provide an osmotic system possessing dual osmotic activity,
`which system comprises a compartment containing a first osmotic composition comprising a drug, and
`preferably an osmagent and/or an osmopolymer, and a second osmotic composition comprising an
`osmagent and an osmopolymer, with the compositions acting in concert for delivering the drug from
`the osmotic device.
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`Yet another object of the invention is to provide an osmotic device having means for high loading
`of a water—insoluble or a slightly water—soluble drug and means for delivering the drug in either
`instance at a controlled rate and continuously overtime.
`—
`Yet another object of the invention is to provide an osmotic device that can deliver a pH
`dependent beneficial agent by providing a neutral medium for delivering the beneficial agent in a finely
`dispersed form-for increasing its surface area and for maximizing the dissolution rate of the beneficial
`agent
`Still yet another object of the invention is to provide an osmotic system for delivering a drug
`having a very low dissolution rate that is the rate~|imiting step for delivering the drug from the system,
`but now can be delivered by using an osmotic composition that functions in situ as a wetting agent and
`a solubiiizing agent for increasing the dissolution rate and the solubility of the drug, thereby enhancing
`its delivery from the osmotic system.
`Still yet another object of the invention is to provide an osmotic system comprising means for
`maintaining a high level of osmotic activity of a polymer used for delivering a beneficial agent from the
`osmotic system.
`’
`Still a further object of the invention is to provide an osmotic, therapeutic device that can
`administer a complete pharmaceutical dosage regimen comprising poorly soluble to very soluble
`agents, at a controlled rate and continuously, for a particular time period, the use of which requires
`intervention only for the initiation and possible termination of the regimen.
`.
`Other objects, features, aspects and advantages of the invention will be more apparent to those
`versed in the dispensing art from the following detailed specification taken in conjunction with the
`figures and the accompanying claims.
`'
`
`Brief Description of the Drawings
`in the drawings, which are not drawn to scale, but are set forth to illustrate various embodiments
`of the invention, the drawing figures are as follows:_
`—
`Figure 1
`is an isometric view of an osmotic device designed for orally administering a beneficial
`agent to the gastrointestinal tract;
`,
`Figure 2 is an opened view of the osmotic device of Figure 1 iliustrating the structure of the
`osmotic device of Figure 1;
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`Figure 3 is an opened view of the osmotic device of Figure 1 illustrating the osmotic device in
`operation and delivering a beneficial agent from the osmotic device;
`,_,;,,.
`Figure 4 is an opened view of the osmotic device of Figure 1 considered with Figure 3 illustrating
`the osmotic device in operation and delivering a major amount ofa beneficial agent from the osmotic
`device;
`Figure 5 shows an osmotic therapeutic device with its wall partially broken away, designed for
`delivering a beneficial agent into a body passageway, such as the ano—rectal and vaginal passageways;
`Figure 6 shows the osmotic device of Figure 5 with a different wall structure;
`Figure 7 shows the osmotic device of Figure 5 depicting a different wall structure than the wall
`structure depicted in Figure 6.
`Figure 8 represents the weight gain as a function of time for a polymer encapsulated in a semi-
`permeable membrane when the encapsulated polymer is placed in water;
`Figure 9 depicts the cumulative amount of drug released from a device comprisingan
`osmopolymer having two different molecular weights;
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`Figure 10 depicts the cumulative amount of drug released from a device using a different set of
`osmopolymers;
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`Figure 1 1 depicts the osmotic pressure curves for a number of osmagent and a number of
`osmopolymer/osmagent compositions;
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`GB 2 140 687 A
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`Figure 12 depicts the cumulative release profile for an osmotic system using two different
`osmopolymers:
`Figure 13 depicts the release rate per hour for an osmotic system different from Figure 9
`containing an osmopolymer having two different molecular weights;
`Figure 14 depicts the cumulative amount released from a single composition device comprising
`only one layer;
`Figure 15 illustrates the in vivo and in vitro cumulative release for one drug delivered by the
`osmotic device;
`Figure 16 illustrates the in vivo and in vitro cumulative release for a different drug delivered by an
`osmotic device.
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`In the drawings and the specification, like parts in related figures are identified by like parts. The
`terms appearing earlier in the specification and in the description of the drawings, as well as
`embodiments thereof, are further detailed elsewhere in the disclosure.
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`Detailed Description of the Drawings
`Turning now to the drawings in detail, which are examples of various osmotic devices provided by
`the invention, and which examples are not to be construed as limiting, one example of an osmotic
`device is seen in Figure 1. In Figure 1,osmotic device 10 is seen comprising a body member 11 having
`a wall 12 and a passageway 13 for releasing a beneficial agent from osmotic device 10.
`in Figure 2, osmotic device 10 of Figure 1
`is seen in opened section. in Figure 2, osmotic device
`10 comprises a body 11, a semipermeable wall 12 that surrounds and forms internal compartment 14,
`that communicates through a passageway 13 with the exterior of osmotic device 10. Compartment 14
`contains a first osmotic composition comprising a beneficial agent 15, represented by dots, and it can
`be from insoluble to very soluble in fluid imbibed into compartment 14, an osmagent 16, represented
`by wavy lines, that is soluble in fluid imbibed into compartment 14 and exhibits an osmotic pressure
`gradient across semi—permeable wall 12 against an external fluid, and, an osmopolymer 17,
`represented by horizontal dashes, that imbibes fluid into compartment 14 and exhibits an osmotic
`pressure gradient across semi—permeable wall 12 against an exterior fluid present in the environment
`of use. Wall 12 is formed of a semi—permeable composition that is substantially permeable to the
`passage of the exterior fluid, and it is substantially impermeable to the passage of the exterior fluid, and
`it is substantially impermeable to the passage of agent 15, osmagent 16 and osmopolymer 17. Semi-
`permeable wall 12 is non—toxic and it maintains its physical and chemical integrity during the delivery
`life of device 10.
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`Compartment 14 also houses a second osmotic composition that is distant from passageway 13
`and in contacting relation with the first composition. The second composition is an expandable driving
`force that acts in co—operation with the first osmotic composition for delivering the maximum amount
`of beneficial agent 15 from osmotic device 10. The second osmotic composition comprises an .
`osmagent 18, that is soluble in fluid imbibed into compartment 14 and exhibits an osmotic pressure
`gradient across wall 12 against an external fluid, blended with an osmopolymer 19 that imbibes fluid
`into compartment 14 and exhibits an osmoticpressure gradient across wall 12 against external fluid.
`Osmopolymers 17 and 19 are hydrophilic water soluble or lightly cross-linked water insoluble
`’
`polymers, and they possess osmotic properties such as the ability to imbibe external fluid, exhibit an
`osmotic pressure gradient across the semipermeable wall against the external fluid, and swell or
`expand in the presence of the fluid. Osmopolymers 17 and 19 are mixed with osmagent 16 and 18 for
`imbibing the maximum volume of external fluid into compartment 14. This fluid is available to
`osmopolymers 17 and 19 to optimize the volumetric rate and for total expansion of osmopolymer-s 17
`and 19. That is, osmopolymers 17 and 19 absorb fluid imbibed into compartment 14 by the osmotic
`imbibition action of osmopolymers 17 and 19 supplemented by the osmotic imbibition action of
`osmagents 16 and 18 for effecting the maximum expansion of osmopolymers 17 and 19 to an
`enlarged state.
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`in operation, the delivery of beneficial agent 1 5 from osmotic device 10 is carried out, in one
`presently preferred embodiment, by (1) imbibition of fluid by the first composition to form a suspension
`in situ and delivery of the suspension through the passageway; and concurrently by (2) imbibition of
`fluid by the second composition causing the second composition to swell and co-operate with the first
`composition for driving the agent suspension through the passageway. According to the operation
`described, the osmotic device may be treated as a cylinder, with the second Composition expanding
`like the movement of a piston for aiding in delivering the agent suspension from the osmotic device.
`Although the shape of the osmotic device as depicted in Figs. 1 and 2 is not a true cylinder, it is
`approximate enough for the following physical analysis. In this analysis, the volume rate delivered by
`the osmotic device F; is composed of two sources: the water imbibition rate by the first composition F,
`and the water imbibition rate by the second composition 0 wherein:
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`Since the boundary between the first composition and the second composition hydrates very
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`Ft=F+Q
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`(1)
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`little during the functioning of the osmotic device, there is insignificant water migration between the
`compositions. Thus, the water imbibition rate of the second composition, 0, equals the expansion of its
`volume.
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`dvp
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`dt
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`=
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`The total delivery rate from the osmotic device is then,
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`dm
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`~—=Ft . C=(F+Q)C
`dt
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`(2)
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`(3)
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`wherein C is the concentration of beneficial agent in the delivered slurry. Conservation of the osmotic
`device volume, V, and the surface area, A, gives equation 4 and 5:
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`V=Vd+Vp
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`A=A,,+Vp
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`(4)
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`(5)
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`wherein Vd and Vp equal the volumes of the first composition and the second composition
`respectively: and wherein Ad and An equal the surface area contact with the wall by the first
`composition and the second composition respectively. ln operation, both V9 and Ap increase with time
`white Va and Ad decrease with time as the device delivers beneficial agent.
`The volume of the second composition that expands with time when fluid is imbibed into the
`compartment is given by equation 7:
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`v,,=$(
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`WH
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`WP
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`l
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`(7)
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`m
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`wherein, W,., is the weight of fluid imbibed by the second composition, Wp is the weight of the second
`composition initially present in the device, WH/WP is the ratio of fluid to initial solid ofthe second '
`20 composition, Vp equals
`'
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`20
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`(1 +
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`VVH
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`WD
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`)
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`VVD
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`e
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`wherein e is the density of the second composition corresponding to WH/Wp. Thus, based on the
`geometry of a cylinder, where r is radius of the cylinder, the area of imbibition is related to the volume
`of the swollen second composition as follows:
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`(8)
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`(9)
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`(10)
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`(1 1)
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`2 WD
`Ap=r2+——— 1 +
`r e
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`W”
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`Wp
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`Ad=A—Ap
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`The fluid imbibition rates into each compartment are:
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`-
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`k
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`F=(—)(Ad And)
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`h k
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`o=i—)(A,, Ann)
`h
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`30 wherein k equals the osmotic permeability of the wall, h equals the wall thickness, A7,, and A79 are the
`osmotic gradients for the first composition and the second composition respectively.
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`The total delivery rate, therefore, is:
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`dm
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`dt
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`k
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`h
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`C A
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`2
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`2 Wu
`Y
`D
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`1+
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`WH
`W
`p
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`2 WD
`A7rd+7r}:2+ —
`"
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`p
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`1+
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`W“
`WP
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`Anp (12)
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`Figures 3 and 4 illustrate the osmotic device in operation as described for Figures 1 and 2. In
`Figures 3 and 4, for osmotic device 10, fluid is imbibed by the first composition at a rate determined by
`the permeability of the wall and the osmotic pressure gradient across the wall. The imbibed fluid
`’
`continuously forms a solution containing beneficial agent, or a solution or of gel osmagent and
`osmopolymer containing beneficial agent in suspension, which solution or suspension in either
`operation is released by the combined operations of device 10. These operations include the solution,
`or the suspension being osmotically delivered through the passageway due to the continuous
`formation of solution or suspension, and by the swelling and increasing volume of the second
`composition, represented by the increase in height of the vertical lines in Figure 3 and 4. This latter
`swelling and increase in volume applies pressure against the solution or suspension thereby aiding the
`first composition and simultaneously causing delivery of beneficial agent to the exterior of the device.
`The first composition and the second composition act together to substantially insure that
`delivery of beneficial agent from the compartment is constant over a prolonged period of time by two
`methods. First, the first composition imbibes external fluid across the wall, thereby forming either a
`solution or a suspension, the latter fraction of which would be substantially delivered at non—zero order
`(without the second composition present), since the driving force decays with time. Second, the
`second composition operates by two simultaneous operations: first, the second composition operates
`to continuously concentrate beneficial agent by imbibing some fluid from the first composition to help
`keep the concentration of beneficial agent from falling below saturation, and second, the second
`composition by imbibing external fluid across the wall continuously increases in volume; thereby
`exerting a force against the first composition and diminishing the volume of benefical agent, thusly
`directing beneficial agent to the passageway in the compartment. Additionally, since the extra solution
`or suspension formed in the first comparment is squeezed out, the osmotic composition cosely
`contacts’ the internal wall and generates a constant osmotic pressure, and therefore a constant delivery
`rate, in conjunction with the second composition. The swelling and expansion of the second
`composition, with its accompanying increase in volume, alongwith the simultaneous corresponding
`reduction in volume of the first composition, assures the delivery of beneficial agent at a controlled rate
`over time.
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`Device 10 of Figures 1 through 4-can be made into many embodiments including the presently
`preferred embodiments for oral use, for releasing either a locally or systemically acting therapeutic
`agent in a gastrointestinal tract. Oral system 10 can have various conventional shapes and sizes such
`as round with a diameter or 3/16 inches to 1/2 inch. In these forms, system 10 can be adapted for
`administering beneficial agent to numerous animals, including warm—blooded animals, humans, avains,
`reptiles and pisces.
`’
`Figures 5, 6 and 7 show another embodiment, an osmotic device 10 designed for placement in a
`body passageway, such as a vagina, or the ano-rectal canal. Device 10 has an elongated, cylindrical,
`self—sustaining shape with a rounded lead end 20, a trailing end 21, and it is equipped with manually
`controlled strings 22 for easily removing device 10 from a biological. passageway. Device 10 is
`structurally identical with device 10 as described above and it operates in a like manner. In Figure 5,
`device 10 is depicted with a semi—permeable wall 23, in Figure 6 with a laminated wall 24 comprising
`an inner semi—permeab|e lamina 25 adjacent to compartment 14, and an external microporous lamina
`26 distant from compartment 14. In Figure 7, device 10 comprises a laminated wall 28 formed of a
`microporous lamina 29 next to compartment 14, and a semi—permeab|e lamina 30 facing the
`environment of use and in laminar arrangement with microporous lamina 29. Device 10 delivers a
`beneficial agent for absorption bythe vaginal mucosa, or the ano-rectal mucosa, to produce an in vivo
`local or systemic effect over a prolonged period of time.
`The osmotic devices of Figures 1 through 7 can be used for delivering numerous agents including
`drugs at a controlled rate independent of the drug pH-dependency, or where the dissolution rate ofthe
`agent can vary between low and high in fluid environments, such as gastric fluid and intestinal fluid.
`The osmotic devices also provide for the high loading of agents of low solubility and their delivery at
`meaningful, therapeutic amounts. And, while Figures 1 through 7 are illustrative of various osmotic
`devices that can be made according to the invention, it is to be understood these devices are not to be
`construed as limiting, as the devices can take a wide variety of shapes, sizes and forms for delivering
`beneficial agents to the environment of use. For example, the devices include buccal, implant, artifical
`gland, cervical intrauterine, ear, nose, dermal, subcutaneous and blood delivery devices. The devices
`also can be sized, shaped, structured and adapted for delivering an active agent in streams, aquariums,
`field, factories, reservoirs, laboratory facilities, hot houses, transportation means, naval means, military
`means, hospitals, veterinary clinics, nursing homes, farms, zoos, sickrooms, chemical reactions, and
`other environments of use.
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`Detailed Description of the Invention
`In accordance with the practice of this invention, it has now been found that osmotic delivery
`device 1 0 can be manufactured with a first osmotic composition and a second osmotic composition
`mutually housed in co-operative relationship in the compartment of the device. The compartment is
`formed by a wall comprising a material that does not adversely affect the beneficial agent, osmagent,
`osrnopolymer and the like. The wall is permeable to the passage of an external fluid such as water and
`biological fluids, and it is substantially impermeable to the passage of agents, osmagents,
`osmopolymers, and the like. The wall is formed of a material that does not adversely affect an animal or
`a host, and the selectively semi-permeable materials used for forming the wall are non—erodib|e and
`they are insoluble in fluids. Typical materials for forming the wall are in -one embodiment cellulose
`esters, cellulose ethers and cellulose ester-ethers. These cellulosic polymers have a degree of
`substitution, D.S., on the anhydroglucose unit, from greater than 0 up to 3 inclusive. By degree of
`substitution is meant the average number of hydroxyl groups originally present on the anhydroglucose
`unit comprising the cellulose polymer that are replaced by a substituting group. Representative
`materials include a member selected from the group consisting of cellulose acylate, cellulose diacylate,
`cellulose trlacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di and tricellulose
`alkanylates, mono, di and tricellulose aroylates, and the like. Exemplary polymers include cellulose
`acetate having a D.S. up to 1 and an acetyl content up to 21%; cellulose acetate having an acetyl
`content of 32 to 39.8; cellulose acetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%;
`cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 35 to 44.8%; and the like. More
`specific cellulosic polymers include cellulose propionate having a D.S. of 1.8 and a propionyl content of
`39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an
`acetyl content of 13 to»15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an
`acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%;
`cellulose triacylates having a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose
`tripalmitate, cellulose trisuccinate, and cellulose trioclanoate; cellulose diacylates having a D.S. of 2.2
`to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioclanoate, cellulose dipentale,
`coesters of cellulose such as cellulose acetate butyrate and cellulose acetate propionate, and the like.
`Additional semi-permeable polymers include ethyl cellulose, cellulose nitrate, acetaldehyde
`dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose
`acetate dimethyl aminoacetate, semi-permeable polyamides, semi—permeable polyurethanes, semi-
`permeable sulfonated polystyrenes, cross—|inked selectively semi-permeable polymers formed by the
`coprecipitation of a polyanion and a polycation as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;
`3,541,005; 3.541.006: and 3,546,142; semi-permeable polymers as disclosed. by Loeb and
`Sourirajan in U.S. Pat. No. 3,133,132; lightly cross—linl.<ed polystyrene derivatives; cross-linked
`p0ly(sodium styrene sulfonatel, cross-linked polylvinylbenzyltrimethyl amonium chloride). semi-
`permeable polymers exhibiting a fluid permeability of 10-5 to 10“ (cc.mi|/cm2.hr.atm) expressed per
`atmosphere 1O‘3 of hydrostatic or osmotic pressure difference across the semi-permeable wall. The
`polymers are known to the art in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020; and in
`Handbook of Common Polymers by Scott, J. R. and Roff, W. J., 1 971 published by CRC Press,
`Cleveland, Ohio.
`The laminated wall comprising a semi-permeable lamina and a microporous lamina are in laminar
`arrangement and they act in concert to form an integral laminated wall, that maintains its physical and
`chemical integrity and does not separate into lamina through the operative agent release history of an
`osmotic device. The semi-permeable lamina is made from the semi-permeable polymeric materials
`presented above, the semi-permeable homopolymers, the semi-permeable copolymers and the like.
`Microporous lamina suitable for manufacturing an osmotic device generally comprises performed
`microporous polymeric materials, and polymeric materials that can form a microporous lamina in the
`environment of use. The microporous materials in both embodiments are laminate to form the laminate
`‘wall. The preformed materials suitable for forming the microporous lamina are essentially inert, they
`maintain their physical and chemical integrity during the period of agent release and they can be
`generically described as having a sponge—|ike appearance that provides a supporting structure for a
`semi-permeable lamina and also provide a supporting structure for microscopic-sized interconnected
`pores or voids. The materials can be isotropic wherein the structure is homogenous throughout a
`cross—sectional area, or they can be anisotropic wherein the structure is non—homogenous throughout
`a cross—sectional area. The pores can be continuous pores that have an opening on both faces ofa
`microporous lamina, pores interconnected through tortuous paths of regular and irregular shapes
`including curved, curved—linear, randomly oriented continuous pores, hindered connected pores and
`other porous paths discernible by microscopic examination. Generally, microporous lamina are defined
`by the pore size, the number of pores, the tortuosity of the microporous path and the porosity which
`relates to the size and the number of pores. The pore size of a microporous lamina is easily ascertained
`by measuring the observed pore diameter at the surface of the material under the electron microscope.
`Generally, materials possessing from 5% to 95% pores and having a pore size of from 10 angstroms to
`100 microns can be used for making a microporous lamina. The pore size and other parameters
`characterizing the microporous structure also can be obtained from flow measurements, where a liquid
`
`’
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`-60
`
`65
`
`10
`
`15
`
`20
`
`25
`
`m
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0240
`
`0240
`
`

`
`
`
`GB 2 140 687 A 7
`
`flux, J, is produced by a pressure difference AP, across the lamina. The liquid flux through a laminate
`with pores of uniform radius extended through the membrane and perpendicular to its surface with
`area A is given by relation 13:
`
`J:
`
`N7r“AP
`
`8nAx
`
`(13)
`
`wherein J is the volume transported per unit timeand lamina area containing N number of pores of
`radius r, 1; is the viscosity of the liquid, and AP is the pressure difference across the lamina with
`thickness Ax. For this type of lamina, the number of pores N can be calculated from relation 14,
`wherein 2 is the porosity defined as the ratio of void volume to total volume of the lamina: and A is the
`cross—sectional area of the lamina containing N pores.
`
`5
`
`10
`
`SA
`
`71:r2
`
`The pore radius then is calculated from relation 15:
`
`Ax 1:
`
`r=81;———
`Ap 5
`
`(14)
`
`10
`
`(15)
`
`15
`
`20
`
`25
`
`wherein J is the volume flux through the lamina per unit area produced by the pressure difference AP
`across the lamina, 11, 5 and Ax have the meaning defined above and -r is the turtuoslty defined as the
`ratio of the diffusional path length in the lamina to the lamina thickness. Relations of the above type are
`discussed in Transport Phenomena In Membranes, by Lakshiminatayanaiah, N, Chapter 6, 1 969,
`published by Academic Press, lnc., New York.
`Asdiscussed in this reference on page 336, in Table 6.13, the porosity of the lamina having pores
`with radius rcan be expressed relative to the size of the transported molecule having a radius a, and as
`the ratio of molecular radius to pore radius a/r decreases, the lamina becomes porous with respect to
`this molecule. That is, when the ratio a/r is less than 0.3, the lamina becomes substantially
`microporous as expressed by the osmotic reflection coefficient or which decreases below 0.5.
`Microporous lamina with a reflection coefficient a in the r