CA1331440C - Dispenser comprising displaceable matrix with solid state properties - Google Patents

Abstract

ABSTRACT OF THE INVENTION
A dispenser is enclosed for delivering a beneficial agent to an environment of use. The dispenser comprising a wall that surrounds an internal space comprising a first means in the dispenser for changing from a dispenser state to an environment of use state on leaving the dispenser, a beneficial agent in the first means, and a second means in the dispenser for aiding in displacing the first means from the dispenser.

Description

" ~t ' 2 MATRIX WITH SOLID STATE PROPERTIES
t 3 FIELD OF THE INVENTION

6 This invention pertains to both a novel and usefut dispenser.
More particularly, the invention relates to a dispenser comprising a 8 semipermeable wall that surrounds, at least in part, a lumen comprising g a displaceable matrix comprising solid state properties and contains a beneficial agent. The lumen contains also an expandable push member 11 for urging the displaceable matrix from the dispenser. In a presently 12 preferred embodiment the dispenser comprises a mouth with an opening ; 13 substantially equal to the cross-sectional area of the lumen for ~
`~ 14 delivering the displaceable matrix comprising the drug to the environ- - ;
ment of use.

` 19 Dispensers for delivering a beneficial agent to the environment `

of use are known to the prior art. For example, one dispenser is 21 disclosed in U.S. Pat. No. 3,995,632 issued to Nakano, Higuchi and 22 Hussain. This patent discloses a dispenser comprising a saturated 23 solution of magnesium sulfate that pushes against a melted composi~
24 tion. The melted composition is squeezed through a passageway from `~

the dispenser. In U. S. Pat. No. 4,251,506 issued to patentee Laby, a 26 device is disclosed consisting of a controlled release composition for 27 administration of a therapeutic agent to a ruminant. The patent ;~-28 discloses in detail a spring for pushing a composition from the -1- ~ `'';;~

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3' dispenser. The use of a spring as a driving force limits the practi-2 cal use of the device as the driving force of a spring diminished by ¦ 3 the distance through which the spring operates. For this device drug ¦ 4 delivery decreases over time as the spring elongates and concurrently weakens. The delivery rate is influenced also by the na~ure of the 6 composition and its interaction with fluid at the interfaced environ-ment of use. The interface provides exterior mechanical action that 8 controls drug release by the environment and not by the device.
g Another dispenser is disclosed in U.S. Pat. No. 4,327,725 by inventors Cortese and Theeuwes. The dispenser disclosed in this patent com-11 prises a hydrogel that urges an aqueous formulation through a passage-12 Wdy from the dispenser. In U.S. Pat. No. 4,350,271 issued to Eckenhoff, 13 a dispenser is disclosed comprising a water swellable composition that 14 pushes a lipophilic fluid from the dispenser. U.S. Pat. No. 4,612,008 issued to Wong, Barclay, Deters and Theeuwes discloses a dispenser `~ 16 wherein an expanding polymer urges a drug formulation comprising an 17 aqueous osmotically active solution from the dispenser. Another dis-18 penser is disclosed by patentees Eckenhoff9 Cortese and Landrau in 19 U.S. Pat. No. 4,595,583. The dispenser disclosed in this patent comprises an expandable aqueous activated osmopo1ymer that urges a ~ ;~
2i heat responsive composition through an orifice from the dispenser.
.
22 The dispenser of the prior art presented above represents an 23 outstanding and pioneering advancement in the dispensing art, and they 24 are additionally useful for dispensing innumerable beneficial agents to an environment of use. Now, this present invention has unexpectedly 26 discovered that a dispenser can be made available comprising a novel 27 and unobvious dispensing means unknown heretofore the delivery a benefi- ;;;
28 cial agent to an environment of use. That is, it has now been disco-:`
1 331 440 ~ ~

vered that a dispenser can be provided comprising means for delivering a bio~affecting beneficial agent in a substantially formulated solid form at a kinetically controlled rate sub-stantially equal to its kinetic rate of release from the dispen-ser. The dispenser ~hereby makes available to a beneficial agent receptor controlled and constant prolonged delivery of a ben-eficial agent according to a preselected built-in optimal pro-gram of beneficial agent presentation.
SUMMARY OF THE INVENTION

Accordingly, in view of the above presentation, it is a principle object of this invention to provide a dispenser ;~
comprising novel means for the controlled delivery of a ben-eficial agent at a rate substantially equivalent to its dispen-ser~controlled rate of release from the dispenser over time.
~he invention is a dispenser for administering a beneficial agent formulation to an animal environment of use, ~
the dispenser comprising: ;
(a) a wall that surrounds and defines an internal lumen, the wall comprising at least in part a semipermeable composition that is permeable to the passage of fluid and is substantially ~ ;
impermeable to the passage of a beneficial agent;
(b) means in the lumen for administering a benefic-ial agent to the animal environment of use, ~` ~

, - 6769~-118 , said means substantially maintaining its physic-al and ch~mical integrity while in the lumen of the dispenser and being substantially non-meltable in thle animal environment of use;
(c) a beneficial agent in the means for administer-ing a beneficial agent; -~d) means for occupying an increasing amount of space in the lumen for urging the means for administering a beneficial agent from the dispenser; and, (e) a mouth in the dispenser comprising a cross-sectional dimension substantially equal to the ~;
cross-sectional dimension of the lumen for .:
~`~ communicating the means for administering the beneficial agent with the environment of use.
; The dispenser delivers a beneficial agent in a solid state that erodes at a controlled rate in a fluid environment of use as it is dispensed from the dispenser. The beneficial ` ~ agent may be in a solid state carrier that diffuses therefrom at ~`

a controlled rate in a fluid environment of use as the carrier is rate-displaced from the dispenser. -`;
A carrier in a substantially solid therapeutically acceptable form can contain a beneficial agent that is leached from the carrier in a fluid environment of use as the carrier is ...... .
~ rate displaced from the dispenser.
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The carrier may be selected from the group consist-ing of a solid and semisolid carrier containing a beneficial agent that is delivered from the carrier by osmotic bursting ¦ into a fluid environment of use over time.
The dispenser may comprise a drug that is soluble or insoluble in an erodible solid or sem3solid carrier and is released therefrom by the erosion of the carrier.
The dispenser may carry a high drug loading, is self-contained, self-starting and self-powered in a fluid environment of use. The dispenser is easy to manufacture, economical to make, and can be used for dispensing a beneficial agent to a warm-klooded animal at a controlled rate over time.
The dispenser may comprise an internal capsule arrangement that makes it easier to manufacture the dispenser at a reduced cost thereby extending the usefulness of the dis-penser for treating humans and domestic animals. The dispenser may comprise an internal lumen containing a carrier comprising a continuous, uninterrupted linear body member symmetrical with -the axis of the lumen, and which carrier is displaced at a continuous, uninterrupted rate from the lumen over time.
The dispenser may comprise a wall that surrounds a lumen with a mouth in the wall having an opening substantially equal to the cross-sectional area of the lumen, and which lumen ~
houses a continuous body member that is urged through the mouth ~ ; i for delivering a beneficial agent to an envionment of use and by - 67~96-118 doing so, a solid formulation of insoluble drug up to 92~ can be aisbursed in the carrier and delivered to the environment of use.
The dispenser may comprise a capsule lumen contain-ing a continuous body member that extends the length of the lu-men except for an expandable driving member for urging the body member from the lumen, a semipermeable wall that surrounds the capsule, and an opening having substantially the same dimensions as the lumen for dispensing the body member from the dispenser.
The dispenser may comprise a semipermeable wall ;~-~
that surrounds in at least a part an internal lumen, which lumen contains a carrier that initially occupies a major portion of the lumen except for a driving member and an optional densif- ~
ier, with the dispenser delivering a beneficial agent by the ~`
combined physical-chemical operations of the driving member urging the displaceable carrier through an opening in the wall to the environment of use.
The dispenser may comprise a dense member for keeping `~
the dispenser in the ~-umen over time, wherein the dispenser administers a complete pharmaceutical dosage regimen for a pro-longed period of time, the use of which dispenser requires intervention only for initiation of the regimen.
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A delivering system can be manufactured as a dis-penser comprising a carrier for a drug wherein the carrier keeps . ~ ~
its physical and chemical integrity during its stay in the -6- ~`

dispenser and changes its physical and/or chemical integrity on its displacement from the dispenser into a fluid environment of use.
A drug delivery system is provided that can deliver a beneficial drug contained in a pharmaceutical carrier that maintains its structure within the delivery system and changes its structure on its delivery into the gastrointestinal tract wherein the pharmaceutical carrier dispenses the drug.
The drug delivery system may comprise a pharmaceutic-` 10 al carrier that is a dispensable composition, that is innocuous, and when upon its displacement from the delivery system sub- ~;
stantially avoids mammalian tissue irritation and interaction with mammalian protein tissue.
The delivery system may comprise an inner capsule, which capsule houses at least one of a hydrophilic or a hydro-phoblc pharmaceutically acceptable carrier comprising insoluble to soluble drugs, and which carrier when the delivery system is in operation is pushed substantially intact and substantially unchanged from the delivery system and changes its physical form on displacement from the delivery system in the environment of use.
The drug delivery device for dispensing a drug to a 1 ~
ruminant may comprise an inner lumen containing a nonmeltable and nonaqueous thermoplastic composition, a space occupying member, and a density member, and which composition comprises ' :' ~ , .

-Ça-1 331 4~n a soluble to insoluble beneficial agent that can be dispensed by the thermoplastic composition after said thermoplastic com-position exits the delivery device. -Other features and advantages of the invention will be more apparent to those skilled in the dispensing art from the following detailed description of the specification, taken in conjunction with the drawings and the accompanying claims.

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1 3 3 1 4 ~ 67696-118 2 In the drawing figures, which are not drawn to scale, but are set 3 forth to illustrate various embodiments of the invention, the drawing 4 figures are as fol10ws:
Figure 1 is a view of a dispenser designed and manufactured for 6 ora11y administering a beneficial agent to a warm-b100ded anima1;
7 Figure 2 is an opened view of the dispenser of Figure 1 through 8 the vertica1 1ength of the dispenser for illustrating the structure of g the dispenser, wherein the dispenser comprises an internal lumen housing a pharmaceutically acceptable carrier that does not melt at 11 the temperature of an animal body, and which carrier comprises a 12 continuous body member extending through a major 1ength of the 1umen, 13 and a space occupying member for pushing the continuous carrier from 14 the 1umen;
Figure 3 is an opened view of the dispenser of Figure 1 taken in 16 conjunction with Figure 2, wherein Figure 3 depicts the dispenser in 17 operation with the carrier formed of a composition that is thermally ~:.
18 stable at the temperature of an animal environment of use being urged 19 from the lumen as the space occupying member consumes space in the lumen and concomitantly urges the continuous carrier from the lumen of 21 the dispenser;
Figure 4 is an opened view taken with Figure 3 depicting!a semi-23 permeable wall that surrounds that lumen with the dispenser in opera~
24 tion wherein the thermally stable carrier severs as it 1eaves the i~
1umen and enters the environment of use from the main body portion of 26 the carrier still contained within the lumen of the dispenser;
27 Figure 5 is an opened view of the dispenser depicting a different 2~ internal structural configuration comprising a nnnmeltable carrier, a f 1 volume consuming member, and a dense member for keeping the dispenser 2 in the rumen of an animal;
¦ 3 Figure 6 is an opened view of the dispenser illustrating another j 4 internal structural arrangement wherein the lumen comprises a carrier that is nonmeltable at animal temperatures, a density member for ~ ;
6 keeping the dispenser in an environment of use and positioned next to 7 the carrier, and means for occupying space in the lumen for pushing : :
8 the carrier through th~ mouth of the dispenser.
g Figure 7 is an opened view of the dispenser through the vertical :
length of the dispenser for illustrating the internal structure of the 11 dispenser comprising an inside wall, an outside wall a carrier that ~ :~12 maintains its physical and chemical integrity inside the dispenser, `~ 13 and means for occupying space in the lumen for urging the carrier from ;~ ;~
14 the dispenser;
lS Figure 8 is an opened view of the dispenser taken in conjunction 16 with Figure 7, wherein the dispenser additionally contains a density 17 member for keeping the dispenser in the rumen of an animal;
18 Figure 9 is an opened view of the dispenser illustrating a diffe~
~: l9 rent arrangement of the means for expanding and occupying space, and the means for keeping the dispenser in the rumen of an animal over ; 21 time;
22 Figure 10 is a cross-section of a laminate provided by the inven~
23 tion comprising an erodible in direct contact with a lamina comprising 24 means for keeping a dispenser in the rumen of a ruminant; ~Figure 11 is a cross-section through a laminate provided by the ~-26 invention comprising an erodible lamina adjacent to a lamina comprising :i 27 a member selected from the group consisting of an osmopolymer and an 28 osmagent;
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9 1 331 4~0 67696-118 F~ure 12 ls a cross-sectlon through a lamlnate provlded by the lnventlon comprising an erodlble lamina in laminar arrange-ment wlth a lamlna comprising means for produclng a gas;
Figure 13 depicts the imbibition pressure measured for varlous osmotic drivlng members;
Figure 14 depicts ~he volume per unlt tlme for a number of composltions;
Figure 15 depicts the release rate ln mg/hr for varlous osmotlc drlvlng member;
Flgure ~6 depicts the volume per unlt tlme plotted against hydratlon H for varlous osmotlc drlvlng members uslng a carboxyvlnyl polymer~ and, Flgure 17 deplcts the volume per unlt tlme plotted agalnst hydratlon H ~or varlous osmotlc drlvlng members uslng a :
poly(oxyethylene~ plus sodlum chloride osmotlc drivlng composltlon. ~
Figure 18 deplcts the release rate per unlt tlme for a ~`
drlvlng composltlon comprlslng Carbopo ~ a carboxyvlnyl polymer (CVP) manufactured by the B. F. Goodrlch Chemlcal Company, U.S.A.
as dlsclosed ln U.S. Patent Nos. 2,798,053 and 2,gO9,462, and sodlum chlorlde~ and, ~.
,Figures 19 to 24 deplct the release rate and the cumulatlve amount released for a series o~ dlspensers provlded by the inventlon.
In the drawlng ~lgures and ln the speciflcatlon, ll~e parts ln related flgures are ldenti~led by llke parts. The terms ~....... ~.

1331~0 -9a- 67696-118 appearlng earlier ln the speclflcatlon and ln the descrlptlon of the drawings, as well as embodiments thereof, are further detalled elsewhere in the dlsclosure.
DBT~IL D DESCRIPTION OE THE DRAWING FIGURES
Turnln~ now to the drawing flgures ln detall, whlch are example~ -,:
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,, ! `:, , ~ ''.`'~'~''', ,' :,, ' , -lo- 1 331 4~7696-118 of new and use~ul dispensers for dispens;ny a beneficial agent, and which examples are not to be construed as 1imitlng, one example o~ a dispenser is depicted in Figure I, identified by the numeral I~. In Figure I, dispenser I0 comprises a body II that surrounds and defines and internal 1umen, not seen in Figure I. Body 11 is formed of a wall j 12 that defined and surrounds a wide-mouth opening 13 for delivering the contents of dispenser Iû to an environment of use.
Figure 2 is an opened view of dispenser I0 for illustrating the structure of the dispenser. Dispenser I0 of Figure 2 comprises, body I0 Il, wall 12 and mouth 13. Wall I2 surrounds an internal lumen I4. In a presently preferred embodiment wall I2 comprises in whole, or at least in part, a semipermeable wall forming compositlon that is sub-stantially permeable to the passage oF an external fluid and it is substantially impenneable to the passage of a beneficial agent and other ingredients contained in iispenser I0. In another embodiIllent, wall 12 can comprise a semipermeable composition, and in part wall I2 can comprise a different composition. Wall 12 is non-toxic and it main-tains its physical and chemical integrity, that is wa11 12 does not erode during the dispensing life of dispenser I0.
Wall 12 surrounds dnd defines an internal lumen 14. Lumen I4 contains carrier means 15 comprlsing beneficial agent 16, represented by dots I6. Lumen 14 also contalns a driving means 17 that is layered and in contact with carrier means 15. Both carrier means 15 and driving means 17 have a shape that corresponds to the internal shape of lumen 14. A passageway 13, also identified For the purpose oF this invention as a mouth, connects ttle outside oF dispenser I0 with lumen I4. A passageway 13 that is a wide-mouth opening ln wall 12, which opening 13 comprises a cross-section that is substantially equal to - 1 331 4~0 the internal cross sectional dimensions of lumen 14. In an optional embodiment, not shown, IYall 12 at opening 13 can curve slightly inward for assisting in governing the movement of carrier means 15 from lumen 1~1 .
Figure 3 depicts dispenser 10 in operation in d biological fluid enviromnellt of use. Dispenser 1~ in Flgure 3 comprises body 11, W.lll 12, mouth 13, lumen 1~, pharmaceutically acceptable carrier means 15, beneficia1 agent 16 in pharmaceutically acceptable carrier means 15, ;~
and space consuming means 17. Pharmaceutically acceptable carrier means 15 keeps its integrity inside lumen 14. That is, carrier means 15 is nonmeltdble at the temperature of use, it does not erode in the lumen, and it does not disintegrate, dissolve, decompose, or hydrolyze ~hile carrier 15 is inside lumen 14. Space consuming member 17, in operation inside lumen 14, absorbs and or imbibes aqueous fluid through wall 12, thereby causing space consumlng means 17 to con-tinuously occupy additional space in lumen 14. This occupying of ~ ~-space by means 17 causes means 17 to apply pressure against carrier 15 and urge it through mouth 13. Carrier 15 as it enters the environment -~
of use at carrier-environment interface 18.
Figure 4 depicts carrier 15 releasing beneficial agent 16 into the environment of use at interface 18. Carrier 15, in the presence of an aqueous-type biological fluid in the environInent of use, re-leases beneficial agent 16 at a controlled rate by the process of erosion, leaching, osmotic bursting, or diffusion. Carrier 15, in the enviromnent bioerodes, disintegrates, dissolves or hydrolyzes as it enters the environment, thereby continuously presenting a new surface of carrier 15 with its beneficidl ~gent 16 to tl1e environment.
~ispenser 10clelivers beneficidl agent 16 dt a controlled rate by the 1331~40 1 combined operations of carrier 15 releasing agent 16 and means 17 2 consuming space in lumen 14 over time.
3 Figure 5 illustrates dispenser 10 comprising in lumen 14 a dense 4 member 19 or densifier that is an important component of dispenser 10 for keeping dispenser 10 in the rumen of an animal over a prolonged 6 period of time. In Figure 5, lumen 14 houses pharmaceutical carrier 7 means 15 in layered contact with a surface of space consuming means 8 17, which latter means is in contact with densifier 19.
9 Figure 6 illustrates another embodiment of dispenser 10 provided by the subject invention. In Figure 6, dispenser 10 is seen in opened 11 view with lumen 14 housing pharmaceutically acceptable carrier means 12 15 in contact with densifier 19. Densifier 19 is in contact with 13 volume consuming means 17. In this embodiment, volume consuming means 17 is positioned distant from mouth 13. The presence of densifier 19 ;~
in dispenser 10 adapts dispenser 10 for use in a rumen. A rumen~
16 retentive dispenser 10 can be manufactured in a variety of sizes and 17 shapes for administering a beneficial agent 16 to a ruminant animal.
18 One presently preferred shape is an elongated or lengthened shape such 19 as a cylinder-like shape, or a capsule like shape with a wide mouth. ;~
For example, for use with sheep, dispenser 10 can embrace an elongated 21 shape and have a diameter of about 0.5 inches to 1 inch (1.3 cm to 22 2.5 cm), and a length of about 0.5 inches to 4 inches (1.3 cm to 10 cm).
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23 For use with cattle, dispenser system 10 comprises a diameter of about 24 O.S inches to 1.5 inches (1.3 cm to 3.8 cm), and a length of about 1 ~-inch to 6 inches (2.5 cm to 15 cm).
26 Figure 7 is an opened view of another embodiment of dispenser 10 27 provided by the invention. In Figure 7, dispenser 10 comprises wall ;~
28 12 that surround internal wide-mouthed capsule 20. In one presently 1 33 1 ~0 pre~erre~ embodlment comprlslng lnternal opened-mouth capsule 20.
Capsule 20 contalns a nonthermo-responsive carrier 15 contalnlng beneficlal agent 16. Capsule 20 further contalns space consumlng means 17 that ls ln layered contact wlth a contactlng surface of carrler means 15. In capsule 20 both carrler means 15 and space , :
consumlng means 17 have a shape that corresponds to the lnternal shape of capsule 20. :~
Flgure 8 ls an opened vlew of another embodlment of a dlspenser 10 provlded by the lnven~lon. In ~lgure 8, dlspenser 10 comprlses an exterlor wall 12 that surrounds capsule ~0. Exterlor wall 12 and capsule 20, ln thls manufacture ~olntly deflne an .
lnternal space that contains pharmsceutlcal carrler means 15 havlng a beneficlal agent 16 dlspensed or dlssolved thereln, a denslty member 19 in contact wlth carrler means lS and a space ~: :
consumlng means 17 in contact wlth the denslty member 19. In thls :
manufacture, space consumlng means 17 ls dlstant from carrler means 15. The carrler means 15, denslty member 19 and space ;
consumlng means 17 all embrace a shape that corresponds to the lnternal shape of the capsule 20.
Figure 9 1~ an opened vlew of another manufacture of ~ :
dlspenser 10 provlded by the sub~ect lnventlon. In Flgure 9, space consumIng member 17 ls ln contact wlth the pharmaceutlcal carrler 15 and denslty member lg is distant from pharmaceutical carrier 15. In a presently preferred embodlment, as space consumlng member 17 fills and takes up space in dispenser 10 lt :
maintalns an l~nlscible boundary at the lnterface defined by means . .~ .

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~13a~ 67696~118 15 and means 17.
Flgure 10 ls an opened vlew of a bilamlna~e provlded by the lnventlon. The lamlnate corresponds to the lnternal arrangement ~' '' ' ~,`

1 33 1 4~0 1 depicted for dispenser 10 depicted in Figure 6. In Figure 10, the 2 lamina comprises an erodible polymeric lamina 15 containing beneficial 3 agent 16, which lamina 15 is in laminar arrangement with lamina 19 4 comprising means for keeping dispenser 10 in a fluid environment of use.
6 Figure 11 is a cross-section of a laminate comprising an erodible 7 lamina 15 containing a beneficial agent 16, which lamina 15 is in 8 contact with a lamina 17 that consumes space inside dispenser 10.
9 Figure 12 is a cross-section through a laminate comprising an erodible lamina 15 containing a beneficial agent 16, which lamina 15 11 is in contact with a lamina 17 that comprises means for consuming 12 space in lumen 14 of dispenser 10.
13 While Figures 1 through 9 are illustrative of various dispensers 14 that can be made according to the invention, it is to be understood -these dispensers are not to be construed as limiting, as the dispensers 16 can take a wide variety of shapes, sizes and forms adapted for delive-17 ring a beneficial agent to different fluid environments of use. For 18 example, the dispenser includes implant, artificial gland, intrau-19 terine, vagina, anal-rectal dispensers and the like. Dispenser 10 can be used in veterinary clinics, farms, zoos, laboratories, on the 21 range, in feed lots, in hospitals, birth clinics, and other environ-22 ments of use.

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24 In accordance with the practice of this invention it has now been found that dispenser 10 can be manufactured with a lumen that houses 26 in cooperative relationship in lumen 14, carrier means 15, beneficial 27 agent 16, space consuming means 17 and in other optional embodiments 28 density member 19. The dispenser 10 is formed by wall 12 comprising a -14- ~ ;

1 33 1 4~0 1 composition that does not adversely affect the carrier, the beneficial 2 agent, the space consuming means, the density means, and other ingre-3 dients such as an osmagent, a gas generating coup1e, and the like that 4 can be housed in dispenser 10. Wall 12, is permeable in at least a part to the passage of an external fluid such as water and biological 6 fluids, and it is substantially impermeable to the passage of benefi-7 cial agents, osmagents, osmopolymers, and the like. The wall com-8 prises a material that does not adversely affect an animal, or host, g or the components comprising the device, and the selectively semiper-meable materials used for forming the wall are non-erodible and they Il are insoluble in fluids. Typical selectively semipermeable materials 12 for forming the wall are in one embodiment cellulose esters, cellulose 13 ethers and cellulose ester-ethers. These cellulosic polymers have a 14 degree of substitution, D.S., on the anhydroglucose unit, from greater than 0 up to 3 inclusive. By degree of substitution is meant the 16 average number of hydroxyl groups originally present on the anhydro~
17 glucose unit comprising the cellulose polymer that are replaced by a 1~ substituting group. Representative compositions include a member 19 selected from the group consisting of cellulose acylate, cellulose ~ 1 diace~ate, cellulose triacylate, cellulose acetate, cellulose diace-21 tate, cellulose triacetate, mono-, di- and tricellulose alkanylates, ~
22 mono-, di- and tricellulose aroylates, and the like. Exemplary poly- ~ -mers include cellulose acetate having a D.S. up to 1 and an acetyl 24 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 26 of 21 to 35X; cellulose acetate having a D.S. of 2 to 3 and an acetyl 27 content of 35 to 44.8%, and the like. More specific cellulosic poly-28 mers include cellulose propionate having a D.S. of 1.8 and a propyl ~ ~
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- :- 1 331 ~0 1 content 39.2 to 45qO and a hydroxyl content of 2.8 to 5.4%; cellulose 2 acetate butyrate having a D.S. of 1.8, an acelyl content of 13 to lS~o 3 and a butyryl content of 34 to 39%; cellulose acetate butyrate having 4 an acetyl content of 2 to 29~, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4~77O; cellulose triacylates having a D.S.
6 of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, ~;
7 cellulose tripalmitate, cellulose trisuccinate, and cellulose tri-8 octanoate; cellulose diacylates having a D.S. of 2.2 to 2.6 such as g cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, co-esters of cellulose such as cellulose 11 acetate butyrate and cellulose acetate propionate, and the like.
12 Additional polymers include ethyl cellulose of various degree of etherification with ethoxy content of from 40% to 55%, acetaldehyde 14 dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellu-lose acetate methyl carbamate, cellulose acetate dimethyl amino-16 acetate, semipermeable polyamides; semipermeable polyurethanes; semi-17 permeable sulfonated polystyrenes; semipermeable cross-linked selec-18 tive polymers formed by the coprecipitation of a polyanion and a 19 polycation as disclosed in U. S. Pat. Nos. 3,173,876; 3,276,586;
3,541,005; 3,541,006, and 3,546,142; semipermeable polymers as dis-21 closed by Loeb and Sourirajan in U. S. Pat. N0. 3,133,132; semiperme- ~`
22 able light1y cross-lined polystyrene derivatives; semipenmeable cross-23 linked poly(sodium styrene sulfonate); semipermeable cross-linked ;;
24 poly(vinylbenzyltrimethyl ammonium chloride); semipermeable polymers exhibiting a fluid permeability of 2.5 X 10-11 to 2.5 X 10-4 (cm2/hr 26 atm) expressed per atmosphere of hydrostatic or osmotic pressure or 27 imbibition pressure difference across the semipermeable wall. The 28 polymers are known to the art in U. S. Pat. Nos. 3,845,770;
-16_ ` ARC 1285 1 3,916,899; and 4,160,020; and in Handbook of Common Polymers by 2 Scott, JO R. and Roff, W. J., 1971, published by CRC Press, Cleveland, OH.
3 Further in accordance with the practice of this invention, it has 4 now been found that internal wall 20 of dispenser 10 can be made as a capsule member. The capsule member generally is tubular shaped and it 6 has a mouth at one end, and at the end distant therefrom it is closed 7 in a hemispherical or dome shaped end. The capsule member serves as a 8 hollow body having a wall 20 that surrounds and defines an interior g compartment 14 provided with an opening 13 for establishing communica-tion with the exterior of the capsule and for fi1ling the capsule.
11 In one embodiment, a capsule is made by dipping a mandrel, such ;
12 as a stainless-steel mandrel, into a batch containing a solution of a ~--13 capsule waTl forming material to coat the mandrel with the material.
14 Then, the mandrel is withdrawn, cooled, and dried in a current of air.
The capsule is stripped from the mandrel and trimmed to yield a capsule 16 with an internal lumen. The materials used for forming the capsule 17 are the commercially available materials including gelatin, gelatin ~ ;-18 having a viscosity of 15 to 30 millipoises and a bloom strength up to 19 150 grams; gelatin having a bloom value of 160 to 250; a composition ;~
gelatin, glycerine water and titanium dioxide; a comprising gelatin, ;
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21 erythrosin, iron oxide and titanium dioxide; a composition comprising 22 gelatin, glycerine, sarbitol, potassium sorbate and titanium dioxide; ~;
23 a composition comprising gelatin, acacia, glycerin and water; water 2¢ soluble polymers that permit the transport of water therethrough and can be made into capsules, and the like.
26 Wall 12 also can comprise a flux regulating agent. The flux 27 regulating agent is a compound added to assist in regulating the fluid ~
28 permeability or flux through the wall 12. The flux regulating agent --`
- 1 7- ~ .
`', 1 3 3 1 '~ ~ A~C 1285 1 can be a flux enhancing agent or a flux decreasing agent. The agent 2 can be preselected to increase or decrease the liquid flux. Agents 3 that produce a marked increase in permeability to fluid such as water, 4 are often essentially hydrophilic, while those that produce a marked decrease to fluids such as water, are essentially hydrophobic. The 6 amount of regulator in the wall when incorporated therein generally is 7 from about 0.01% to 20% by weight or more. The flux regulator agents 8 in one embodiment that increase flux include polyhydric alcohols, g polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols, and the like. Typical flux enhancers include polyethylene 11 glycol 300, 400, 600, 1500, 4000, 6000 and the like; low molecular 12 weight glycols such as polypropylene glycol, polybutylene glycol and 13 polyamylene glycol: the polyalkylenediols such as poly(l,3-propanediol), 14 poly(l,4-butanediol), poly(l,6-hexanediol), and the like; aliphatic diols such as 1,3-butylene glycol, 1,4-pentamethylene glycol, 1,4-16 hexamethylene glycol, and the like; alkylene triols such as glycerine, 17 1,2,3,-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol and the l;ke;
18 ester such as ethylene glycol dipropionate, ethylene glycol butyrate, 19 butylene glycol dipropionate, glycerol acetate esters, and the like. ;
Representative flux decreasing agents include phthalates substituted 21 with an alkyl, and alkoxy or with both an alkyl and alkoxy group such `~
.~ , .
22 as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, 23 and ~di(2-ethyl-hexyl) phthalate], aryl phthalates such as triphenyl 24 phthalate, and butyl benzyl phthalate; insoluble salts such as calcium ~ -25 sulphate, barium sulphate, calcium phosphate, and the like; insoluble 26 oxides such as titanium oxide; polymers in powder, granule and like 27 form such as polystyrene, polymethylmethacrylate, polycarbonate, and 28 polysulfone; esters such as citric acid esters esterfied with long -18~

- 1 331 4~0 1 chain alkyl groups; inert and substantially water impermeable fillers;
2 resins compatible with cellulose based wall ~orming materials, and the 3 like.
4 Other materials that can be used to form the wall 12 for impar-ting flexibility and elongation properties to the wall, for making 6 wall 12 less-to-nonbrittle and to render tear strength, include 7 phthalate plasticizers such as diberzyl phthalate, dihexyl phthalate, 8 butyl octyl phthalate, straight chain phthalates of six to eleven carbons, di-isononyl phthalate, di-isodecyl phthalate, and the like.
~ The plasticizers include nonphthalates such as triacetin, dioctyl 11 azelate, epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl ~;
12 trimellitate, sucrose acetate isobutyrate, epoxidized soybean oil, and ;~
13 the like. The amount of plasticizer in a wall when incorporate ~
14 therein is about 0.01% to 20% by weight, or higher. ~ ;
Representative of means for manufacturing space consuming means 16 17 for urging pharmaceutically carrier means 15 from lumen 14 through `~
17 mouth 13 are at least one of a member selected from the group consis- ~-18 ting of an osmopolymer, an osmagent and a gas generating couple.
19 Exemplary of an osmopolymer that can be used for the present purpose `~
is a hydrogel. The hydrogel in the dispenser comprises a shape that 21 corresponds to the internal shape of lumen 14. The hydrogel composi- -~
22 tion is noncross-linked or optionally cross-linked and it possesses ;~
23 osmotic properties such as the ability to imbibe an exterior fluid ;~
24 through semipermeable wall 12, and exhibit an osmotic pressure gradient across semipermeable wall 12 against a fluid outside 26 dispenser system 10. The materials used for forming the space con-27 suming member that are swellable and expandable, are polymeric mate-28 rials neat, and polymeric materials blended with osmotic agents that ` ~ 4 0 1 interact with water or biological fluid, absorb the fluid and swell or 2 expand to an equilibrium state. The polymer exhibits the ability to 3 retain a significant fraction of imbibed fluid in the polymer molecular 4 structure. The polymers in a preferred embodiment are gel polymers that can swell or expand to a very high degree~ usually exhibiting a 2 6 to 50 fold volume increase. The swellable, hydrophilic polymers, also 7 know as osmopolymers can be noncross-linked or lightly cross-linked.
8 The cross-links can be covalent or ionic bonds with the polymer g possessing the ability to swell in the presence of fluid, and when cross-linked it will not be dissolved in the fluid. The polymer can 11 be of plant, animal or synthetic origin. Polymeric materials useful ~`
12 for the present purpose include poly(hydroxyalkyl methacrylate) having 13 a molecular weight of from 5,000 to 5,000,000; poly(vinylpyrrolidone) ;
14 having a molecular weight of from 10,000 to 360,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohol) 16 having a low acetate residual; a swellable mixture of agar and car- `
17 boxymethyl cellulose; a swellable composition comprising methyl cellu-18 lose mixed with a sparingly cross-linked agar; polyethers having a 19 molecular weight of 10,000 to 6 million; a water-swellable copolymer produced by a dispersion of finely divided copolymer of maleic anhyd-21 ride with styrene, ethylene, propylene, or isobutylene; water swellable 22 polymer of N-vinyl lactams; and the like.
I ' 1 ~ ' ~
23 Other gelable, fluid imbibing and retaining polymers useful such 24 for forming the hydrophilic, expandable push member include pectin ;
25 having a mo1ecular weight ranging from 30,000 to 300,000; polysaccha-2~ rides such as agar, acacia, karaya, tragacanth, algins and guar;
27 Carbopol~, an acrylic acid polymer, a carboxyvinyl polymer, sometimes 28 referred to as carboxypolymethylene, a polymer of acrylic acid cross-, .

~ -20-1 3 ~ 1 4 4 O ARC 1285 1 linked with a polyallyl ether of succrose, as described in U. S. Pats.
2 Nos 2,798,053 and 2,909,462 and available as Carbopols~ 934, 940 and 3 941, and its salt derivatives; polyacrylamides; water-swellable indene 4 maleic anhydride polymers; Good-rite~ polyacrylic acid having a mole-cular weight of 80,000 to 200,000; ~'olyox~ polyethylene oxide polymers 6 having a molecular weight of 100,000 to 5,000,000; starch graft co-7 polymers; Aqua-Keep~ acrylate polymers with water absorbability of 8 about 400 times its original weight; diesters of polyglucan; a mixture g of cross-linked polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone);
zein available as prolamine; poly(ethylene glycol) having a molecular 11 weight of 4,000 to 100,000, and the like. In a preferred embodiment, 12 the expandable member is formed from polymers and polymeric composi-13 tions that are thermoformable. Representative polymers possessing 14 hydrophilic properties are known in United States Patents No. `
3,865,108; 4,002,173; 4,207,893; 4,327,725, and in Handbook of Common 16 Polymers, by Scott and Roff, published by Cleveland Rubber Company, ~-17 Cleveland, Ohio.
18 The osmagent that can be used for the purpose of providing space19 consuming means 17 comprise inorganic and organic compounds that ~
exhibit an osmotic pressure gradient against an external fluid across -~ ~`
21 semipermeable wall 12. Osmagents are also known as osmotically effec-22 tive compounds and as osmotically effective solutes. The osmagent 23 imbibes fluid from the outside of dispenser 10 into lumen 14 causing ~ -24 it to produce a solution or a suspension that continuously occupies ~-more space in lumen 14. As more fluid is imbibed into lumen 14, it 26 exerts d pressure against pharmaceutically acceptable carrier 15 27 pushing it From dispenser 10~ Osmotically effective compounds useful ~ `
28 for the present purpose include inorganic and organic salts, poly-':' -'','.' ,''. ' ','.

; ~

.;
' 1 saccharides, carbohydrates, and the like. Representative solutes i 2 include magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, lithium chloride, potassium su1fate, sodium carbo-4 nate, sodium sulfate, lithium sulfate, sodium sulfate, potassium acid 5 phosphate, calcium lactate, tartaric acid, lactose, fructose, mannitol, 6 sorbitol, and mixtures thereof. The osmotically active compound is 7 initially present in lumen 14 in excess and it can be in particle, 8 crystal, pellet, powder or granule form. The osmotic pressure of an g osmotic compound can be measured with a commercially available osmometer 10 identified as Vapor Pressure Osmometer, Model 2B, available from 11 Hewlett-Packard, Avondale, Penna. The osmotic pressure in atmospheres 12 of osmagents suitable for this invention will be greater than zero ~ 13 atm9 generally from zero atm up to 500 atm, or higher. ~
`~ 14 The osmotically effective compound that can be blended homo- ~-geneously or heterogeneously with the swellable polymer, to form a 16 push member 17, are the osmotically effective solutes that are soluble 17 in fluid~ imbibed into the swellable polymer, and exhibit an osmotic 18 pressure gradient across the semipermeable wall against an exterior 19 fluid. Osmotically effective osmagents useful for the present purpose include magnesium sulfate, magnesium chloride, sodium chloride, j~ 21 lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, 22 sorbitol, inositol, succrose, glucose, and the like. The osmotic !j ' ,;, 23 pressure in atmospheres, atm, of the osmagents suitable for the inven-24 tion will be greater than zero atm, generally from greater than zero ``~ 25 atm up to 500 atm, or highèr. The swellable, expandable polymer, in i~ .26 addition to providing a driving source 17 for urging carrier 15 con-27 taining beneficial agent 16 from dispenser 10, further serves to 28 function as a supporting matrix for an osmotically effective solute.
~ .

;

1 The osmotic solute can be homogeneously or heterogeneously blended 2 with the polymer to yield the desired expandable, member 17. The 3 composition in a presently preferred embodiment comprises at least one 4 polymer and at least one osmotic solute. Generally, a composition -~
will comprise about 2070 to 90% by weight of polymer and 80% to 10~ by 6 weight of osmotic solute, with a presently preferred composition 7 comprising 35% to 75% by weight of polymer and 65% to 25% by weight of 8 osmotic solute.
g The gas generating couple operable as space occupying means 17 is, in a presently preferred embodiment, an effervescent couple or 11 composition. The gas generating couple comprises at least one 12 preferably solid acidic material and preferably solid basic material 13 that dissolve and react in aqueous fluid that enters the dispenser to 14 produce carbon dioxide. The gaseous generation of carbon dioxide leads to the volume displacement of carrier 15 containing beneficial 16 agent 17 from dispenser 10. The gas generating couple can be present 17 in powder, crystalline, granular, compressed forms, and the like. The 18 acidic or acids that can be used include organic acids such as malic, l9 fumaric, tartaric, itaconic, maleic, citric, adipic, succinic and mesaconic, and the corresponding anhydride such as itaconic anhydride, ~ ;
21 and citriconic anhydride. Also inorganic acids such as sulfamic or 22 phosphoric, and the like can be used for gas generation. Acid salts 23 such as the salts of organic foods can be used including monosodium 24 citrate, potassium acid tartrate, and potassium bitartrate, The basic compounds include metal carbonate and bicarbonate salts such as alkali 26 metal carbonates and bicarbonates, or alkaline earth carbonates and 27 bicarbonates. Exemplary materials include the alkali metals lithium, -28 sodium, and potassium carbonate and bicarbonate9 and the alkaline ; .:
-23- ~
;','''''~;

1 3~ 1 440 ARC 1285 1 earth compounds magnesium and calcium carbona~e or bicarbonate. Also 2 useful are ammonium carbonate, ammonium bicarbonate and ammonium ses-3 quecarbonate. The combination of certain of these acids and bases 4 resul~s in a more rapid gas production or effervescence when contacted by ~ater. In particular, either citric acid or a mixture of citric 6 acid and tartaric acid and sodium bicarbonate give a rapid gaseous 7 reaction that can be used for urging carrier 17 from dispenser 10. It 8 will be understood the amount of acidic and basic materials in a 9 couple can vary over a wide range to satisfy the amount of gas genera-tion need to urge carrier 17 from dispenser 10. The essentially 11 anhydrous or dry couple is preferably substantially stoichiometrically 12 balanced to produce a combination that generates carbon dioxide.
13 Also, the acid and base materials can be used in any convenient pro-14portion between 1 to 200 parts and 200 to 1 part on a weight basis to produce the desired results. In addition, the gas generating material 16 can be a substance that generates gas on contact with water such as 17 calcium carbide or carbure.
18Pharmaceutically acceptable carrier means 15 in a presently 19 preferred embodiment maintains its physical and chemical integrity inside lumen 14 of dispenser 10. The phrase "maintains its physical 21 and chemical integrity inside lumen 14", used for the purpose of this 22 invention, denotes a carrier formulation that does not substantially 23 undergo change in lumen 14 of dispenser 10. That is, carrier formula-24 tion 15 does not hydrolyze, erode, disintegrate or dissolve in lumen 1~ during operation of dispenser 10. The expression "nonmeltable", as 26 used for the purpose of this invention means carrier 15 substantially 27does not melt inside lumen 14 of dispenser 10. That is, carrier 15 28 inside lumen 14 substantially does not change from a solid to a liquid ':; ~'`

., ' 1 ~3 1 ~40 1 state. Carrier formulation 15, on its delivery from dispenser 10 can, 2 in a fluid biological environment of use, such as the gastrointestinal tract of a warm-blooded animal undergo hydrolysis in the acidic or basic pH of the tract, it can undergo surface erosion, disintegrate, dissolve, be hydrolyzed by enzymes, digested by bacteria or fungi~ and 6 the like.
7 Exemplary of carrier formulation means 15 generically include a ;
8 member selected from the group consisting of a polyester, polylactide, g polyacetal, polyorthoester, polyorthocarbonate, and the like.
Representative of more specific carrier formulations 15 include a - :, 11 member selected from the group consisting of polyglycolic acid 12 exhibiting a Tm of 230C wherein Tm is the melting point, polydiglyco-13 lide having a Tm of 230C, polylactic acid having a Tm of 180C, 14 polydilactide having a Tm of 180C, polydimethylglycolic acid with a Tm of 240C, polycaprolactone having a Tm of 63C, polyalkylene 16 adipate wherein the alkylene group comprises 10 carbons having a Tm of 17 77C, polylactide-co-glycolide, and the like.
18 Representative of additional compositions for forming carrier 19 means 15 comprise polyanhydrides, polyanhydride polymers of sebacic ;
20 and azelaic acid, hydrophobic polycarbolyic acids having one ionizable .., 21 carboxylic hydrogen for each 8 to 22 total carbon atoms, bioerodible 22 polymers that innocuously disintegrate or breakdown as a unit structure 23 on release by dispenser 10 such as a hydrophobic polycarboxylic acid ~ ;
24 having a repeating backbone unit of 8 to 22 carbon atoms for each pendant carboxylic hydrogen; a bioerodible polyvalent ion cross-linked 26 polyelectrolyte with a polyvalent ion selected from the group consis-27 ting of aluminum, barium, cadmium, calcium, copper, iron and zinc with 28 the polyelectrolyte selected from the group consisting of carrageenan9 t`

~ , . .

1 3 ;~ 0 1 pectic acid, pectinic acid and the like; a polyester of the 2 formula [-0-W-CO]y wherein W is an alkylene of 1 to 4 carbons and y is 3 a whole number to provide a polymer having a molecular weight of 4,000 4 to 100,000; a polyorthoester selected from the group consisting of poly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran), 6 poly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran), poly(l,4-cyclohexane 7 dicarbinyl-2,2-dioxtetrahydrofuran), poly (2,2-dioxohexamethylene-1,3-8 dioxolane), poly(2,2-dioxa-trans-2-methyl-cylclohexane-1,4-diethylene-9 2-pyrrolidone), poly(2,2-dioxa-us, trans-1,4-cyclohexane-dimethylene-2-thiocane), and the like. Representative of additional compositions 11 for fonming carrier means 15 include polyamino acid, polypeptide, 12 polyglutamate, polyglutamic acid, polylysine, and the like. - -13 Representative of additional polymeric materials for providing 14 carrier means 15 are a hydrophilic polymer selected from the group, consisting of a poly(alginate), poly(carrageenan), poly(guar gum), 16 poly(gum agar), poly(gum arabic), poly(gum ghatti) poly(gum paraya), ;~
.
17 poly(gum tragacanth), poly(tamarid gum), poly(xanthan gum) and the 18 like. The hydrophilic polymeric material, when used for carrier means 19 15, comprises a different polymeric composition when a hydrophilic polymeric material is used for space consuming member 17, or when 21 carrier means 17 and space consuming means 17 are in contact with each 22 other.
Carrier means 15, in additional operative embodiments, can be 24 manufactured by (1) compressing water insoluble materials into a shape that corresponds to the internal shape of lumen 14. For example, ;~
26 carrier means 15 can comprise a tableted, an elongated stick-like 27 shape, or the like. Carrier means 15, in its additional operative 28 embodiments, maintains its integrity in lumen 14, and on its exit from ,' , .f~
~ 1 331 4 4() ARC 1285 1 dispenser 10 disintegrates, or the like, in the fluid environment of 2 use. In this manufacture, carrier means 15 can comprise polymerized particulate composition of matter comprising polyethylene, polypropylene, 4 cellulose acetate, ethylcellulose, polysulfone, cellulose acetate butyrate, microcrystalline cellulcse, and the like.
6 Carrier means 15, in another embodiment, can be manufactured from 7 (2) substantially insoluble organic and inorganic substances. Carrier 8 15, in this embodiment, keeps its shape in lumen 14 but loses its g shape in an environment of use. Representative of insoluble organic and insoluble inorganic ;olids used for this purpose comprise a member `
11 selected from the group consisting essentially of calcium carbonate, -12 calcium sulfate, diatomaceous earth, clay, silicon dioxide, pulverized :~
13 glass, and`the like.
14 A carrier means 15, with operative properties can be manufac-tured, in one embodiment, with good properties for engaging in contac-16 ting relation wall 12 or wall 20, by compounding a member selected 17 from group (1) with a member selected from group (2). For example, 18 materials selected from (1) and (2) are mixed with each other and with 19 a lubricant or an oil and then with a small quantity of a member selected from the group consisting of a swellable polymer such as 21 gelatin, hydroxypropylmethylcellulose, pectin, and the like, and with -22 a disintegrating agent such as solks floc, and the like. The presence 23 of the disintegration agent in carrier 15 on carrier 15's exposure to 24 the environment of use results in the break up of the carrier into ~;
smal1 parts with a concurrent delivery of the beneficial agent 16 in ;~
26 the environment of use.
27 The expression active agent 16 as used herein, includes any 28 beneficial agent, or beneficial compound, that can be delivered from r~
1 ~ 1 440 1 the dispenser to produce a beneficial and useful result. The agent ' 2 can be insoluble ~o very soluble in the pharmaceutically acceptable carrier 15. The term active agent includes algicide, antioxidant, air 4 purifier, biocide, bactericide, catalyst, chemical reactant, disinfec-tant, fungicide, fermentation agentl fertility inhibitor, fertility ~' 6 promoter, germicide, plant growth promoter, p1ant growth inhibitor, preservative, rodenticide, sterilization agent, sex sterilant, and the 8 like.
g In the specification and the accompanying claims, the term bene-ficial agent also includes drug~ The ter,m "drug" includes any physio-~; 11 logically or pharmacologically active substance that produces a local 12 or systemic effect, in animals, including warm blooded mammals; humans13 and primates; avians; household, sport and farm animals; laboratory 14 animals; fishes; reptiles and zoo animals. The term "physiologicalIy",1S as used herein, denotes the administration of a drug to produce 16 generally normal levels and functions. The term "pharmacologically", 17 denotes generally variations in response to the amount of drug admini- -18 stered to the host. See Stedman's Medical Dictionary, 1966, published 19 by Williams and Wilkins, Baltimore, MD.
The active drug that can be delivered includes inorganic and 21 organic compounds without limitation, including drugs that act on the ;
:
22 peripheral nerves, adrenergic receptors, cholinergic receptors, nervous ;
23 system, skeletal muscles9 cardiovascular system, smooth muscles, blood ~;`
24 circulatory system, synaptic sites, neuroeffector junctional sites, endocrine system, hormone systems, immunological system, reproductive 26 system, skeletal system, autacoid systems, alimentary and excretory 27 systems, inhibitory of autocoid systems, alimentary and excretory 28 systems, inhibitory of autocoids and histamine systems. The active ~
:, .
-28~

1 3 3 1 ~ 4 0 1 drug that can be delivered for acting on these recipients include 2 anticonvulsants, analgesics, antiparkinsons, anti-inflammatories, 3 calcium antagonists, anesthetics, antimicrobials, antimalarials, anti-4 parasites, antihypertensives, antihistamines, antipyretics, alpha-adrenergic agnoist, alpha-blockers, biocides, bactericides, bronchial 6 dilators, beta-adrenergic blocking drugs, contraceptives, cardiovascular 7 drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, 8 electrolytes, hypnotics, hormonals, hyperglycemics, muscle contrac-g tants, muscle relaxants, opthalmics, psychic energizers, parasympatho-mimetics, sedatives, sympathomimetics, tranquilizers, urinary tract 11 drugs, vaginal drugs, vitamins, nonsteroidal anti-inflammatory drugs, 12 angiotensin converting enzymes, polypeptide drugs, and the like.
13 Exemplary drugs that are very soluble in water and can be de-14 livered by the dispenser of this invention include prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, potassium chloride, 16 mecamylamine hydrochloride, procainamide hydrochloride, amphetamine 17 sulfate, benzphetamine hydrochloride, isoproteronol sulfate, metham-18 phetamine hydrochloride, phenmetrazine hydrochloride, bethanechol 19 chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexethyl chlo-21 ride, phenformin hydrochloride, methylphenidate hydrochloride, cimeti-22 dine hydrochloride, theophylline cholinate, cephalexin hydrochloride, 23 and the like.
24 Exempl~ry drugs that are poorly soluble in water and that can be delivered by the dispenser of this invention include diphenidol, 26 meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, ;;-27 thiethylperazine maleate, anisindone, diphenadione erythrityl tetrantrate, ;
28 digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethia- ;~

.' r~

O

1 zide, chlorpropamide, tolazamide, chlormadione acetate, phenaglycodol, 2 allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, 3 erythromycin, progestins, esterogenic, progestational, corticosteroids, 4 hydrocortisone, dydrocortiocosterone acetate, cortisone acetate, tri-S amcinolone, methyltesterone, 17 beta-estradiol, ethinyl estradiol, 6 ethinyl estradiol 3-methyl ether, pednisolone, 17 beta-hydroxypro-7 gesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, 8 norethisterone, norethiederone, progesterone, norgesterone, norethyno-9 drel, and the like.
Examples of other drugs that can be delivered by the dispenser 11 include aspirin, indomethacin, naproxen, fenoprofen, sulindac, `~
12 indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, 13 atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, ~-~
14 chloropromazine, methyldopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of alpha-methyldopa hydrochloride, theophylline, calcium gluco-16 nate, ketoprofen, ibuprofen~ cephalexin, erythromycin, haloperidol, 17 zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, 18 diltiazem, milrinone, captopril, madol, quanbenz, hydrochlorothiazide, 19 ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin, alolofenac, mefenamic, flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine, :
21 nicardipine, felodipine, lidoflazine, tiapamil, gallopamil amlodipine, `~
22 mioflazine, lisinolpril, enalapril, captopril, ramipril, endlapriat, 23 famo~idine, nizatidine, sucralfate, etintidine, tertatolol, minoxidil, 24 chlordiazepoxide, chlordiazepoxide hydrochloride, diazepan, amitriptylin hydrochloride, impramine hydrochloride, imipramine pamoate, and the 26 like. The beneficial drugs are known to the art in Phanmaceutical 27 Sciences, 14th Ed., edited by Remington, (1979) published by Mack .. :- - ~:
28 Publishing Co. Easton, PA: The Drug, The Nurse, The Patient, Including '; -:;'.
-30~

1 331 ~U

1 Current Drug Handbook, by Falconer, et al, (1974-1976) published by 2 Saunder Company, Philadelphia, PA; Medicinal Chemistry, 3rd Ed., Vol 1 3 and 2, by Burger9 published by Wiley-Interscience~ New York; and in 4 Physicians' Desk Reference, 38 Ed., (1984) published by Medical Economics Co., Oradell, NJ.
6 The drug can be in various forms, such as uncharged molecules, 7 molecular complexes, pharmacologically acceptable salts such as hydro_ 8 chloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrite, 9 borate, acetate, maleate, tartrate, oleate and salicylate. For acidic drugs, salts of metals, amines or organic cations; for example, quar-11 ternary ammonium can be used. Derivatives of drugs such as ester~ -12 ethers and amides can be used. Also~ a drug that is water insoluble 13 can be used in a form that is water soluble derivative thereof to 14 serve as a solute, and on its release from the device, is converted by enzymes, hydrolyzed by body pH or other metabolic processes to the 16 original biologically active form. The amount of beneficial agent in 17 a dispenser generally is about from 0.05 ng to 10 9 or more, with 18 individual dispenser containing, for example, 25 ng, 1 mg, 5 mg, 10 19 mg, 25 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.0 9, 1.2 9, 1.5 9, 4.5 9, 7.5 9, and the like, for administering to a human.
21 The term beneficial agent as used herein also comprises medicines 22 or drugs, nutrients, vitamins, food supplements and other agents that 23 are administered to farm animals. The dispenser can house various 24 amounts of beneficial agents for administering to a farm animal, `~
usually from 75 ng to 50 9 for farm animals, for example, 75 ng, 1 mg, 26 5 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1.5 mg, 2 9, 5 9, 10 9, 25 9, 27 and the like. A single dispenser can be administered to a farm animal, 28 for example to a ruminant, or more than one dispenser can be adminis~

:

1 tered to a ruminant during a therapeutic program. Dispensers can be 2 provided that have a rate of release from 5 m;crograms to 5 grams per 3 day, or higher for a farm animal.
4 Representative of beneficial medicaments that can be dispensed to a farm animal using ~he delivery system 10 of this invention include 6 anthelmintics such as benzimidazole, mebendazole, levamisole, albenda-7 zole, cambendazole, fenbendazole, parbendazole, oxfendazole, oxybenda-8 zole, thiabendazole, tichlorfon, praziquantel, thiophanate, morantel, 9 morantel tartrate, pyrantel, pyrantel tartrate, methoprene, and the like; antiparasitic agents for the management of endoparasites and 11 ectoparasites, such as avermectin and ivermectin, as disclosed in ~:
12 United States Patents No. 4,199,569 and 4,389,397 both assigned to 13 Merck & Co., and in Science, Vol 221, pp 823-828, 1983, wherein said 14 ivermectin antiparasitic drugs are disclosed as useful for aiding in : -:-controlling commonly occurring infestations in farm animals, such as ~ :
16 roundworms, lung worms and the like; and said ivermectin also being 17 used for the management of insect infestations such as grub, lice, :~
18 mange mite, mite, ticks, larve, flies such as larve warble fly, dung~
19 breeding fly, larve and flies in the excreta of animals; and the like, ;;
with delivery system administering from 5 micrograms per kilogram per 21 day (5 ~g/kg/d), to 250 milligrams per day (250 mg/kg/d), to cattle . ~ ~
22 for establishing avermectin, including ivermectin, blood levels; anti- .~
23 microbial agents such as chloretetracycline, oxytetracycline, tetra- .
~: 24 cycline, strep~omycin, dihydrostreptomycin, bacitracins, erythromycin, ~ 25 chlortetracycline, ampicillins, penicillins, cephalosporins, and the : 26 like; sulfa drugs such as sulfamethazine, sulfathiazole, sulfonamides, 27 and the like; macrolides such as erythromycin, spiramycin, tylosin and :~
.. :
28 the like; nitrofurans; antibiotics; ionaphores such as lasalocid, ~ ~

: -32 j~:

", k ~

1 3~1 440 ~, 1 salinomycin, virginamycin, ronnel and the like; growth-stimulants such 2 as Monesin~ sodium, and Elfazepam~; defleaing agents such as dexamtha-3 zone and flumethazone; rumen fermentation manipulators; antibloat ~! 4 agents such as organo-polysiloxanes; growth promoting agents; minerals;
mineral salts and trace elements formulations such as magnesium, 6 copper, cobalt, iron, manganese, molybdenum, zinc, selenuim, copper oxide, copper sulfate, cobalt salt, copper salt, selenium salt, 8 selenium disulfied, sodium selenite, inorganic, organic compounds, g cobalt oxide, and the like; hormone growth supplements such as sti1-bestrol; growth efficiency factor, beta-agonist such as denbuterol; ~-11 vaccines such as bovine diarrhea vaccine; vitamins such as vitamin A, 12 B-group, C, D, E, K and the like; antienteritis agents such as furazo-: , 13 lidone; nutritional supplements such as lysine, lysine monhydrochloride, 14 methionine, me~hionine salts, amino acids, peptides, and the like; ~-beneficial alpha agonists, and the like. ~;
16 Pharmaceutically acceptable carrier means 15 on leaving lumen 14 17 of dispenser 10 delivers a beneficial agent 16 to a gastrointestinal 18 tract by rate controlled kinetics. For example the pharmaceutical l9 carrier means 15 can deliver a beneficial agent 16 as a rate controlled by diffusion, by osmosis, by osmotic bursting, by solution leaching, 21 by so1ubilization by cross-link cleavage, by solubilization of carrier ;~
22 means 15, by hydrolysis, by solubilization of carrier means 15 by ionization of pendant groups, by solubilization of carrier means 15 by -~
24 protonation of pendant groups, by solubilization by backbone cleavage, by biodegradation, by bioerosion, by enzymatic action, by oxidation, 26 by reduction~ by proteolysis, by displacement, by dissolution, by 27 disintegration, and the like.
28 The density member 19, also referred to as densifier 19, used in j -33- ~

1 33 1 ~0 dispenser 10, is dense enough to rekain dispenser I0 in the rumen-reticular sac of a ruminant. Density member I9 lets dispenser 10 remain in the rumen over a prolonged period of time rather than let-4 ting it pass into the alimentary tract and be eliminated therefrom.
As system 10 remains in the rumen9 beneficial active agent 16 is 6 delivered by system 10 at a controlled rate to the ruminant over time.
7 Generally, dense member 19 will have a density of from about 0.8 to 8, 8 or higher, with the density in a presently preferred embodiment ex-9 hibiting a specific gravity of from 1.2 to 7.6. For the ruminants, cattle and sheep, it is presently preferred dense member 19 exhibit a `~
11 density such that there is a resulting system density of about 3 gm/ml. Materials that have a density that can be used for forming ~;
13 dense member 19 include iron, iron shot, iron shot coated with iron ~
14 oxide, iron shot magnesium alloy, steel, stainless steel, copper ; `
oxide, a mixture of cobalt oxide and iron powder, and the like. Dense 16 member 19 in delivery system 10 can embrace different embodiments.
17 For example, dense member 19 can be machined or cast as a single, 18 solid piece made of stainless steel having a density of 7.6 gm/ml.
19 The solid member is made having a curved shape that corresponds to the internal shape of system I0. The solid member can have an axially 21 aligned bore that extends through the length of the unit member. In 22 another embodiment, dense member 19 can compose a plurality of dense 23 pellets or lamella. Density member 19 is described above consists of `
24 means having a specific gravity greater than the fluid environment of use for keeping dispenser 10 in the fluid environment over time. ;
26 The semipermeable wall forming composition can be applied to the 27 exterior surface of a dlspenser alone or in laminar arrangement by ~
28 molding, air spraying, dipping or brushing with a semipermeable wall ~;

-3~-1 33 1 ~0 1 forming composition. Other and presently preferred techniques that 2 can be used for applying the semipermeable wall are the air suspension 3 procedure and the pan coating procedures. The air procedure consists 4 in suspending and tumbling the lumen forming components in a current of air and a semipermeable wall forming composition until the wall 6 surrounds and coats the components. The procedure optionally can be 7 repeated with a different semipermeable wall forming composition to 8 form a semipermeable capsule laminated wall. The air suspension 9 procedure is described in U.S. Patent No. 2,799,241; J. Am. Pharm.
Assoc., Vol 48, pp 451 to 459, 1979; and ibid, Vol 49, pp 82 to 84, 11 1960. Other standard manufacturing procedures are described in Modern 12 Plastics Encyclop dia, Vol 46, pp 62 to 70, 1969; and in 13 Pharmaceut~cal Sci_nces, by Remington, 14th Edition, pp 1626 to 1678, 14 1970 published by Mack Publishing Co., Easton, PA. In those manufac-tures wherein the wall is coated by air suspension or by pan coating 16 techniques, mouth 13 is formed in the wall by one of a number of 17 techniques such as laser cutting, milling, sawing, drilling, and the 18 like, wherein the device or the mouth-cutting tool is in motion or is 19 stationary.
Exemplary solvents suitable for manufacturing the wall 12 include 21 inert inorganic and organic solvents that do not adversely harm the 22 materials, the capsule wall, the beneficial agent, the carrier compo-23 sltion9 the expandable member, the dense member, and the final dispenser.
24 The solvents broadly include members selected from the group consis-ting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic 26 hydrocarbons, halogenated solvents, cycloaliphatics, aromatics, 27 heterocyclic solvents and mixtures thereof. Typical solvents include 28 acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, .

` 1 3 3 1 ~ 4 0 ARC 1285 .
1 butyl alcohol, methyl isobutyl ketone, methyl propyl ketone, n-hexane, 2 n heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichlo-ride, carbon tetrachloride, nitroethane, nitropropane, tetrachlor-ethane, ethyl ether, isopropyl ether, cyclohexane, cyclo-octane, ben-6 zene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, ¦ 7 and mixtures thereof such as acetone ~and water, acetone and methanol, ¦ 8 acetone and ethyl alcohol, methylene dichloride and methanol, and g ethylene dichloride and methanol.
DESCRIPTION OF EXAMPLES OF THE INVENTION
11 The following examples are merely illustrative of the present 12 invention and they should not be considered as limiting the scope of 13 the invention in any way, as these examples and other equivalents 14 thereof will become apparent to those versed in the art in the light ~ -f the present disclosure, the drawings and the accompanying claims.

17 The operation of a dispenser 10 manufactured according to the 18 invention is set forth in this example. The volume delivery rate of 19 the drug formulation compartment 14 is equal to the volume rate of water imbibition (dV/dt) into the osmotic agent formulation 21 compartment 17 expressed by equation (1) as follows~

A (1) 24 ~
25 where k is the water permeability of the semipermeable wall, h is the ~ -26 thickness of the wall, A is the wall surface exposed to the osmotic -27 process, and ~ is the osmotic pressure difference across the wall.
!28 The geometrical shape considered here is as shown in Figure 13, with ~;

.

~ 1331~0 1 flat bottom and cylindrical body. The volume rate of water imbibition 2 can be related to the total surface area for water transport A from 3 the end and cylindrical sections from equations (2) and (3):
4 A = ~r2 + 2 rQ (2) where Q is the height of the osmotic formulation.
67A = ~r2 + 2 V (3) where V is the volume of osmotic formulation. The volume expansion of the osmotic driving member equals VO VH (4) 11 where VO and VH are, respectively, the volumes of dry osmotic agent formulation and water imbibed. Alternatively, (4) can be written 13 V = p + p (S) where pO is the density of dry osmotic agent formulation, WO and WH

17 are the weights of osmotic agent and water imbibed9 and PH is the density of water.

Rearranging terms within the equations, the following equation results:

22 WO ( WH Po) (6) and 24 A = ~r2 + 2r p (I + ~ PH) Therefore, the volume rate of water imbibition is expressed by:

27 ~ ~ ~lrr + r (I + P Ir) O J ~1l (a) -37- ~
,~

1 and the release rate of the drug from dispenser 10 becomes:
2 dm dV
~F Cd ~ (9 4 where Cd is the concentration of drug in the carrier phase.
Equation (9) considered in conjunction with (8), allow for 6 numerous delivery rates and drug programs derived from system 10 7 geometry and the osmotic pressure ~ programmed in the dispenser as a 8 function of time.
g For development of the example, Eq. (10) will be substituted in the subsequen~ equations.
11 H = WH (10) 13 Based on the composition of the carrier phase Cd system 10 14 geometry and osmotic properties of the driving chamber 17, simulations of the release rate profile were calculated as shown in Figure 14 for 16 a given wall composition and various values of Mo from 4 to 8 gram.
17 ~ is given as in equation (11) and in equation (12) based on ~
18 experimental data are presented herein, ;19 ~ O for H < 0.1 (11) :~
~(H~ = exp ~A(Ln H)2 + B lnH + C] for 0.1<H<1 (12) 21 Substituting equation (12) and equation (13) in equation (1), 22 equation 14 results as follows:

24 A (H) = ~r2 + 2 (1+ p H) p `
,-26 -dtV = h A (H) . a~ (H) (14) ~`~

28 rn addition, (15) holds for the volume of absorbed water VH
~;

, . ~;,.

1 ~H WO
2 VH = p = H p (15) 3 Since the volume of formulation displaced (16) is related to H by (15), 4 dV = VH (16) 6 it follows that (17) results 8 dH = H . h . A (H).~(H) = f(H) (17) 9 The solution of this differential equation will result in H(t) which can be substi~uted in (14) to yield the release rate. The ~;
11 solution to equation (17) was solved by numerical integration, resul- :
12 ting in the simulations for the release rates given in Figure 14. The :13 numerical integration of (17) is obtained from (18) as follows:

l4 ~ f(H~

17 The final value at shutdown for system 10 for Hf and t~ is given by 18 equation (19): :~

Hf = H Wdc (19) 21 Here PdC and Wdc are the density and weight of the drug compartment . ., 22 14. The function H(t) is obtained by finding the time t; associated ~
23 with the hydration value Hj. The final value of H, Hf equation (19), ~``
24 can be reached after m equal steps ~H, such that (20) results, and ~ -:
also ( 21).
26 ~ H. = f (20) J m :~
27 ;
28 . :

-39- ~

1 3~ 1 4 40 ARC 1285 Hj(tj) = ~ ~ Hj (21) 3 The time tj associated with Hj is calculated from equation (22) where 4 ~ is the average value of expression (17) between the start and send of the interval i: -~

7tj = ~ ~tj (22) `

gHere ~tj is given by (23) t. = - (23) f(H) 13 From (9), t15), (16) and (23), it follows then that the delivery rate ,~ `, 14 ~ (t) as a function of time is given by (24). .
W
16~ t (t) = PH (~t ) Cd (24) 19EXAMPLE 2 ;
The delivery rate of dispenser 10 can be programmed by using the ;
21 factors as described in Example 1~ In this example, a formulation ;
22 comprising an osmagent is described with its effect on the release of ;~;
23 an!active agent. A formulation of osmagent comprises a blend of 24 sodium carbopol 934 and sodium chloride in a 70:30 ratio. The osmotic pressure ~ at four hydration values H was measured and as listed in 26 Table 1, and can be described as follows: ~ ;
27 ~ = 400 atm for H < 0.1 28 ~ = exp~-0.1516(ln H)2-0.3962 ln(H) + 5.7340] for 0.1 <H <1 ,r~
1 33 1 ~4(-) `

2 Osmotic Pressure of Carbopol (70)/NaCl(30) Formuiation 4 ~ (atm) Hydration (H) S 400 0.25 7 340 0.75 8 310 1.00 : 9 EXAMPLE 3 - ~
11Following the above described procedures, a dispens~r 10 was ma~e ~-12with the parameters listed in Table 2. The dispenser comprises a wall ~ .
, 1312 having a total weight of 1.8 9 and comprising 91% cellulose acetate 14 butyrate having an acetyl content of 38.1% and 9% polyethylene glycol lS 400.

17 Wall thickness: h = 0.51 mm (20 mil) 18 Wall radius: r = 0.93 mm 19 Push tablet height: L = 1.8 cm ~
2t) Mass of drug compartment: Wdc = 4.36 gr ;:
21 Density of drug compartment: PdC = 1.0 22 Density of push compartment: Qp = 1.4 23 Drug loading in carrier phase Cd = 0.06 gr/ml i;~
24 Wall permeability k = 2.28 10-5 cc.mil/cm2 hr 25Figure 15 shows the release rate from the dispenser comprising 26 weights of osmagents from 4 to 8 grams.
27Additional studies were performed to show the rate of release :~1 28 from dispenser lt) with a series of osmagents. The imbibition pressure 41- ;~

r~ 1 3 ~ I 4 4 1 of three compositions were measured as a function of hydration and 2 plotted in Figure 13. In Figure 13, the line with triangles denotes 3 Polyox~ coagulant~polyethylene oxide) with a molecular weight of about 4 5,000,000 plus 29X sodium chloride, the line with squares denotes Polyox~ coagulant with a molecular weight of 5,000,000; and the line ~ ;
6 with circles denotes Carbopol~ polymer, a carboxyvinyl polymer with a 7 molecular weight of 100,000 and 29% sodium chloride. The data in 8 Figure 13 can be described by the following equation (Y) wherein 9 ~ (atm) = C X HN and the constants C and N are given in Table 3. ;

11 Composition ;~
of Osmagent C N

13 P`olyox Coagulant 96 -1.38 14 71% Carbopol + 29% NaCl 88 _0.51 ;
71% Polyox ~ 29% NaCl 315 -0.54 16 Given the above osmotic pressures the volumetric delivery rates ;~
17 dV/dt, equation (14) Examples can calculated for a cylindrically shaped 18 bolus by equation (14) as function of degree of hydration ~H).
19 The calculation shows that the release rate can be programmed by varying the diameter or radius of the system, the thickness of the 21 layer of osmagent and selection of the osmagent. Figures 1~, 16 and 22 17 show the volumetric delivery rate normalized to the initial rate of 23 H - 0.1 as a function of hydration (H) for various compositions of 24 osmagent, diameter of the system, thickness and weight of the osmo-polymer layer. The data indicate that the volumetric rates can be 26 decreasing or increasing as a function of the degree of hydra~ion.

-42- ~;

, ' ,`.

.
In this example a dispenser was provided with the following 3 properties:
1. Osmotic driving member: 71% polyoxyethylene mol. wt.
5,000,000 plus 29% NaCl.
2. Wall composition: cellulose acetate butyrate with k = 6.13 X 10-5 cm.mil/hr.atm.
3. Weight of drug layer; 4.36 9.
g 4. Weight of drug in drug layer: 6%.
5. Dispenser's diameter: 1.86 cm.
11 6. Release rate for different weights of osmotic driving 12 members, WO, between 4 to 8 9 are plotted in Figure 18.

14 A dispenser for the control1ed delivery of ivermectin is made as follows: first, 190 9 of poly (2.2-dioxo-trans-1,4-cyclohexane di-16 methylene tetrahydrofuran) is heated in a laboratory Teflon~ pan 17 equipped with a surface thermome~ric to about 150C, and then 14 9 is 18 added thereto and the two components blended into a homogeneous compo-19 sition. Next, the composition is molded into a cylindrical shape and cooled to room temperature. Next, the bioerodible composition is 21 placed into a wide mouth capsule previously charged at its closed 22 bottom first with a 30 9 stainless steel density member and then with ~ i~
23 an expandable driving member. The driving member comprises 2 9 of 24 sodium chloride and 5 9 of sodium salt of polyacrylic acid available ;~
2 as Carbopol~ 934P previously pressed into a tablet. The tablet is 26 formed using a 18.2 mm tableting tool and about 3 1/2 tons of compres-27 sion force. The tablet compresses a final shape that corresponds to 28 the internal shape of the opening of the capsule. The expandable ~ ;

- 1 331 ~0 1 tablet has a surface in contact with the pharmaceutical invermectin 2 composition. Next, the capsule is coated on its exterior surface up 3 to its mouth by dipping it into wall forming composition. The wall 4 forming composition comprises 1.8 9 of 91% cellulose acetate butyrate and 9 X polyethylene glycol 400. The wall is applied from a ~O wt/wt 6 solution of methylene chloride methanol 90:10 v/v solvent system. The 7 wall coated dispenser is dried at about 25 to 30C for 24 hrs. The 8 dispenser provided by this example delivers invermectin to a rumen 9 over a long period of time.

11 A dispenser is made according to the procedure set forth in 12 Example 5, with the manufacturing conditions as set forth, except that 13 in this example the pharmaceutically acceptable carrier comprises a 14 condensation copolymer of 3,9-bis(ethylidence)-2,4,8,10-tetraoxospiro~5.5]
undecane and 1,6-hexanediol. The copolymer can be prepared according 16 to the synthesis described in U.S. Pat. No. 4,304,767.

18 A dispenser is made according to the procedure set forth in 19 Example 5, with the manufacturing conditions as set forth, except that -~
in this example the pharmaceutically acceptable carrier comprises a -21 condensation copolymer of 3,9-bis(ethylidine)-2,4,8,10-tetraoxospiro~5.5]
22 undecane and the diol ethylene glycol. The copolymer can be prepared 23 according to the synthesis described in U.S. Pat. No. 4,304,767.

A dispenser is made according to the procedure set forth in 26 Example 5, with the manufacturing conditions as set forth, except that 27 in this example, the pharmaceutically acceptable carrier comprises a 28 polymer of polyols and ketene acetals having a functionality of two or .
~ -44-` 1 3;~ 1 4~0 1 more as disclosed in U.S. Pat. No. 4,304,767, and in J. Cont. Rel.
2 Vol. 4, pp 87-95, 19867 Excipients used to catalyze a controlled 3 surface erosion process of the pharmaceutically acceptable carrier are 4 disclosed in J. Cont. Rel. Vol. 1, pp 225-232, 1985.

6 A dispenser is made according to the procedure set forth in 7 Example 5, with the manufacturing conditions as set forth, except that 8 in this example, the pharmaceutically acceptable means comprises the g hydrophobic copolymer poly(2,2-dioxo-trans-1,4-cyclohexane-dimethylene tetrahydrofuran-2,2-dioxo-1,6-hexamethylene tetrahydrofuran) prepared 11 according to the synthesis described in U.S. Pat. No. 4,~93,709.

13 A dispenser system is prepared as follows: first, the body 14 section of a capsule is positioned with its mouth in an upright posi~
tion, and a dense stainless steel element inserted into the hemipheri-16 cal end of the capsule. The dense element is machined and its shape 17 made to match the internal shape of the capsule. Next, a layer of an -18 expandable, swellable composition is charged on top of the dense 19 element. The composition comprises 25% by weight of sodium chloride and 75g by weight of poly(ethylene oxide) having a molecular weight of 21~ 200,000. The expandable forming ingredients are blended in a commer-22 cial blender with heat for 20 minutes to yield a homogeneous composi- ;;~
23 tion. The warm composition is charged into the capsule forming a 24 layer that occupies about 1/3 of the capsule, next a pharmaceutical carrier comprising an active agent is charged into the opened capsule.
. .;
26 Next, 90 9 of polylactide having a molecular weight of about 40,000 is 27 dissolved in xylene and 3.5% levamisole is added thereto. The blend .: .
28 is charged into the capsule to form a homogeneous mass and vacuum ;

}

1 33 1 ~0 1 dried at 60C. Then, a solution of cellulose acetate, 15 wt %, with 2 an acetyl content of 39.8%, is prepared in a methylene chloride methanol 3 solvent system and the outside surface of the capsule coated with a 4 semipermeable wall while maintaining the mouth open. The wall is applied by dipping it into the coating solution for 15 times, first 6 for a S second dip, then for two ten second dips, then for a 30 second 7 dip and then for 1 minute per dip wil:h an intervening 5 minute drying 8 period. Following the dipping the delivery dispenser is dried at room g temperature, 72F, about 22C, for 5 days. The procedure applies about a 2 mm thick semipermeable wall.
; 11 EXAMPLE 11 12 A dispenser is provided comprising a tube-shaped walled dispenser 13 comprising an opened end and a closed end. The wall comprises 50%
14 cellulose acetate butyrate, 45% poly(sulfone) and 5~ citric acid ester `
selected from the group consisting of acetyl tributyl citrate and 16 acetyl tri-2-ethyhexyl citrate. The pharmaceutically acceptable 17 carrier comprises the polyhydroxyacetic ester, polyglycolic acid, 18 having the beneficial agent impramine hydrochloride dispersed therein.
19 The space consuming means comprises poly(ethylene oxide) having a 20 molecular weight of about 3,000,000 and 30g by weight of potassium 21 chloride.
22 EXAMPLE 12 ~;
23 A dispenser is provided according to claim 10, wherein the dispen ~ ;
24 ser comprises a hydrophilic expandable member comprising a 70:30 ratio of sodium carbaxymethylcellulose to sodium chloride, lubricated with 26 1~ magnesium stearate compressed using 10,000 lbs of force in a Carver~
27 laboratory press.

, ~',.

2 A dispenser 10 was made for ascertaining the release rate 3 profiles wherein the dispenser comprises an osmotic driving member 4 that pushes a stick-shaped drug composition from the dispenser. The drug composition comprised the insoluble drug ibuprofen, 85~. The 6 drug stick shaped composition was macle by wet granulation. The compo-7 sition comprised 92.5% of cellulose acetate, polyethylene oxide and 8 hydroxypropylmethylcellulose in equal amounts, then the granules were g blended in a powder of hydroxypropylcellulose and hydroxy propyl-lQ methylcellulose. The final drug stick layer comprised 85~ ibuprofen, 11 10% hydroxypropylcellulose, 3% hydroxypropylmethylcellulose, 1% poly-12 ethylene glycol.
13 Accompanying Figures lg and 20 represent the release rate in 14 mg/hr and the cumulative amount released in percent from a dispenser comprising a drug composition comprising 84.7% ibuprofen, 2.6~ of 16 cellulose acetate and polyethylene glycol in equal percent. 10.3%
17 hydroxypropylcellulose and 2.4% hydroxypropylmethylcellulase; an 18 osmotic push compartment comprising 71~ polyethylene oxide and 29%
19 sodium chloride; and a wall comprising 80% cellulose acetate having ~` 20 an acetyl content of 39J8%~ 10% polyethylene glycol 3350, and 10% ;
21 hydroxypropylmethylcellulose. The release rate for the dispenser as s 22 indicated in Figures 19 and 20 was measured in artificial intestinal . .
23 fluid. Figures 21 and 22 depict the release rate for the dispenser in 24 operation in artificial gastric fluid.
Figures 23 and 24 depict the release rate pattern for a dispenser 26 in artificial ga!stric fluid. The drug composition in the dispenser 27 comprised 90 wt % acetaminophen, 2 wt % polyvinyl pyrrolidone cross-28 linked, 5 wt % microcrystalline cellulose, 1 wt % polyvinylpyrrolidone l33l4~n 1 and 2 wt % magnesium stearate; the osmotic driving composition com-2 prised 71 wt % polyethylene oxide having a mol. wt of 5,000,000 and 29 3 wt % sodium chloride; and a wall comprising 90 wt % cellulose acetate 4 having an acetyl content of 39.8~ and 1070 polyethylene glycol having a mol. wt of 3350.
6 Inasmuch as the foregoing specification comprises preferred em- : :
7 bodiments of the invention, it is understood that variation and modi-8 fications may be made herein in accordance with the ;nventive principles g disclosed, without departing ~rom the scope of the invention.

-: ;:

18 ;:~
19 '' ''' Z3 ~
24 :

-48- ; :

Claims (20)

1. A dispenser for administering a beneficial agent formulation to an animal environment of use, the dispenser comprising:
(a) a wall that surrounds and defines an internal lumen, the wall comprising at least in part a semipermeable composition that is permeable to the passage of fluid and is substantially impermeable to the passage of a beneficial agent;
(b) means in the lumen for administering a beneficial agent to the animal environment of use, said means substantially maintaining its physical and chemical integrity while in the lumen of the dispenser and being substantially nonmeltable in the animal environment of use;
(c) a beneficial agent in the means for administering a beneficial agent;
(d) means for occupying an increasing amount of space in the lumen for urging the means for administering a beneficial agent from the dispenser; and, (e) a mouth in the dispenser comprising a cross-sectional dimension substantially equal to the cross-sectional dimension of the lumen for communicating the means for administering the beneficial agent with the environment of use.

2. The dispenser for administering the beneficial agent formu-lation to an animal environment according to claim 1, wherein the means in the lumen for administering the beneficial agent comprises a cross-sectional dimension substantially equal to the internal cross-sectional dimension of the lumen.

3. The dispenser for administering the beneficial agent formu-lation to an animal environment according to claim 1, wherein the means in the lumen for administering the beneficial agent is urged intact through the mouth, when the dispenser is in operation.

4. The dispenser for administering the beneficial agent formu-lation to an animal environment of use according to claim 1 wherein the means in the lumen for administering the beneficial agent com-prises a hydrophobic composition.

5. The dispenser for administering the beneficial agent formu-lation to an animal environment of use according to claim 1 wherein the means in the lumen for administering the beneficial agent com-prises a hydrophilic composition that is a different composition than the means for occupying space.

6. The dispenser For administering the beneficial agent formu-lation to an animal environment of use according to claim 1 wherein the means in the lumen for administering the beneficial agent is urged through the mouth into the animal environment and bioerodes therein.

7. The dispenser for administering the beneficial agent formu-lation to an animal environment of use according to claim 1 wherein the means in the lumen for administering the beneficial agent is delivered from the dispenser and is hydrolyzed in the animal environ-ment.

8. The dispenser for administering the beneficial agent formu-lation to an animal environment of use according ot claim 1 wherein the means in the lumen for administering the beneficial agent is delivered from the dispenser and is solubilized in the animal environ-ment.

9. The dispenser for administering the beneficial agent formu-lation to an animal environment of use according to claim 1 wherein the means in the lumen for administering the beneficial agent is urged from the dispenser and dissolved in the animal environment.

10. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 1, wherein the means in the lumen for administering the beneficial agent disintegrates in the animal environment.

11. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 1, wherein the means administers the beneficial agent by at least one process comprising diffusion, osmosis, osmotic bursting, solution leaching, solubilization, hydrolysis, enzymatic digestion, displacement and dissolution.

12. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 1, wherein the animal environment of use 13 a ruminant.

13. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 1, wherein the animal environment of use is a human.

14. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 1, wherein the lumen comprises means for maintaining the dispenser in an animal environment of use over time.

15. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 14, wherein the means for maintaining the dispenser in an animal environment of use over time exhibits a density greater than the density of the biological fluid in the environment of use.

16. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 14, wherein the means for maintaining the dispenser in an animal environment of use over time exhibits a specific gravity greater than the density of the biological fluid in the environment of use.

17. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 1, wherein the dispenser further comprises an internal capsule positioned between the internal lumen and the means for admin-istering the beneficial agent.

18. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 17, wherein the capsule comprises means for maintaining the dispenser in an animal environment of use over time.

19. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 18, wherein the means for maintaining the dispenser in an animal environment of use over time exhibits a density greater than the density of the biological fluid in the environment of use.

20. The dispenser for administering the beneficial agent formulation to an animal environment of use according to claim 18, wherein the means for maintaining the dispenser in an animal environment of use over time exhibits a specific gravity greater than the density of the biological fluid in the environment of use.