CA1319071C - Dispenser with movable matrix comprising a plurality of tiny pills - Google Patents

Abstract

ABSTRACT OF THE INVENTION
A dispenser is disclosed for delivering tiny pills to an environment of use. The dispenser comprises a wall that surrounds an internal space comprising a first means in the dispenser for chang-ing from a dispenser state to an environment of use state on leaving the dispenser, tiny pills in the first means, and a second means in the dispenser for aiding in displacing the first means for the dispenser.

Description

~319Q7 I ARC 1439 1 D~SPENSER WITH MOVABLE MATRIX
23 COMPRISING A PLURALrTY_OF TINY PILLS

8 This invention pertains to both a novel and useful dispenser.
g More particularly, the invention relates to a dispenser comprising a IO wall that surrounds a lumen. The lumen contains a movable matrix I1 containing a plurality of tiny pills, which tiny pills contain a 12 beneficia1 agent. The lumen contains also a driving member for 13 pushing the matrix from the dispenser. The dispenser comprises a 14 mouth ;n the wall having a cross-sectional area substantially equal to that of the lumen for delivering the matrix containing the tiny pills 16 to an environment of use.

18 Dispensers for delivering a beneficial agent to an environ-19 ment of use are known to the prior art. For example, one dispenser is disclosed in United States Patent No. 3,995,632 issued to patentees 21 Nakano, Higuchi and Hussain. This patent disc10ses a dispenser com-22 prising a saturated solution of magnesium sulfate that pushes against 2~ a melting composition. The melting composition is squeezed through a 24 small passageway from the dispenser. In United States Patent No.
4,251,506 issued to patentee Laby, a device is disclosed consisting of 26 a controlled release composition for administering a therapeutic agent 27 to a ruminant. The patentee discloses in detail a spring for pushing 28 a composition from the dispenser. The use of a spring as a driving - 1 3 ~

1 force limits the practical use of the device~ as the driving force of 2 a spring diminishes by the distance through which the sprlng operates.

3 For this device, drug delivery decreases over time as the spring 4 elongates and, concurrently, weakens. The delivery rate is inFluenced also by the nature of the composition and its interaction with fluid 6 as the interfaced environment of use. The interface provides exterior 7 mechanical action that controls drug released by the environment and 8 not by the device.
9 Another dispenser is disclosed in United States Patent No.
4,327,725 by the inventors Cortese and Theeuwes~ The dispenser dis-11 closed in this patent comprises a hydrogel that urges an aqueous 12 formulation through a passageway from the dispenser. In United States 13 Patent No. 49350,271 issued to Eckenhoff, a dispenser is disclosed 14 comprising a water swellable composition that pushes a lipophilic fluid from the dispenser. United States Patent No. 4,612,008 issued 16 to Wong, Barclay, Deters and Theeuwes discloses a dispenser wherein an 17 expanding polymer pushes a drug formulation comprising an aqueous 18 osmotically active solution from the dispenser~ Another dispenser is 19 disc10sed by patentees Eckenhoff, Cortese and Landrau in United States Patent No. 4,595,583. The dispenser disc10sed in this patent com-21 prises an expandable, aqueous activated osmopolymer that urges a heat 22 responsive composition through an orifice of predetermined limited 23 dimensions from the dispenser.
24 The release of uncoated pellets of drug and coated pellets of drug is disclosed by patentee Blythe in United States Patent 26 No. 2,738,303. In this patent the delivery system disclosed consists 27 essentially of a capsule containing uncoated pellets and coated pel-28 lets of drug having varying thickness. On release of the pellets from ~ 3 ~ 9 ~ ~ ~ 67696-123 the capsule the uncoated pellets provide an initial amount of drug and the coated pellets provide drug over a period of time.
Another delivery system is disclosed by patentee Sheth et a:l in United States Patent Nos. 4,140,775 and ~,167,558. The systems disclosed in these patents consist essentially oE a tablet formed of a compressed polymer containing dispersed drug. The system is hydrodynamically balanced for remaining in the stomach for releasing drug over tirne.
The delivery systems of the prior ar-t presented above represen-t an outstanding and pioneering advancement in the dispensing art and they are, additionally, useful for dispensing innumerable beneficial agents to an environment of use. Now, this present invention has discovered unexpectedly that a dispenser can be made available comprising a novel and an unobvious dispensing means unknown heretofore for delivering a bene-ficial agent to an environment of use. That is, it now has been discovered that a dispenser can be provided comprising means for delivering a bio-affecting beneficial agent at a kinetically controlled rate substantially equal to its kinetic rate of release from the dispenser. The dispenser thereby makes available to a beneficial agent receptor controlled and constant prolonged delivery of a beneficial agent according to a preselected built-in optimal program of beneficial agent presentation.

SUMMA~Y OF THE INVENTIO~
In view oE the above presentation it 1s a principle object of this invention to provide a dispenser comprising novel means for the controlled delivery of a beneficial agent preferably , , ~ 3 ~ s~

at a rate substantially equivalent to its dispenser-controlled rate of release from the dispenser over time.
The invention provides a dispenser for administering a beneficial agent, the dispenser comprising: (a) a wall that surrounds an internal lumen, the wall comprising a composition that is permeable to fluid and impermeable to a beneficial agent;
(b) means in the lumen for containing a plurality oE tiny pills, said means maintaining its physical and chemical integrity while in the lumen; (c) a plurality of tiny pills in the means, the tiny pills comprising: (1) a beneficial agent; and, (2) a wall that surrounds the beneficial agent; (d) means in the lumen Eor pushing the means comprising the tiny pills from the dispenser; and, (e) a mouth in the dispenser comprising a cross-section substantially equal -to that of the lumen for delivering the tiny pills from -the dispenser.
The dispenser preferably exhibits all of the practical benefits of controlled and continuous administration of a drug to animals and to humans over a prolonged period of time.
The dispenser provides a reservoir which erodes at a controlled rate in a fluld environment of use as it is dispensed from the dispenser and concurrently with the erosion releases tiny pills to the environment of useO The tiny pills are delivered at a controlled rate in a fluid environment of use as a tiny-timed pill carrier is rate displaced from the dispenser.
The dispenser preferably comprises a pharmaceutically acceptable carrier selected from the group consisting of solid and semi-solid carriers containing tiny pills that are released from '~,;~, L3~7~

the carrier into a fluid environment oE use as the carrier is rate displaced from the dispenser. The dispenser is selE-contained, self-starting and self-powered in a Eluid environment of use.
The dispenser preEerably has a matri~ containing tiny pills, which matrix on its release from the dispenser disintegrates and releases the tiny pills. The dispenser may comprise a reservoir composition that houses a multiplicity oE
tiny pills, which tiny pills comprise a drug that is from poorly soluble to very soluble in an aqueous media, which drug now can be delivered at a rate controlled by the dispenser, at a continuous rate for a particular time period, the use of which dispenser requires intervention only for initiation of the drug delivery regimen.
The dispenser preferably comprises a reservoir and a plurality of tiny pills, which two members function as a cooperative uni-t for administering from low to high doses of a drug to the gas-trointestinal tract at a controlled rate over a prolonged period of time. The dispenser internal lumen may contain a carrier comprising a continuous linear body member symmetrical wlth the axis of the lumen, which carrier contains the plurality of tiny pills with the carrier displaced at a continuous, uninterrupted rate from the lumen 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 dispenser for treating humans and domestic animals.
The dispenser may comprise a capsule lumen containing a 3 ~ 67696-123 body member comprising the plurality of tiny pills, which body member extends the length of the lumen except Eor the area occupied by an expandable driving member Eor urging the body member from the lumenr 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 comprising tiny pills and initially occupies a major portion of the lumen, except Eor a driving member and an optional densiEier, with the dispenser delivering a beneEicial agent contained in the tiny pills by the combined physical-chemical operations of -the driving member urging the displaceable carrier through an opening in the wall of the environment of use.
The dispenser may comprise a dense member for keeping the dispenser in the lumen over time, wherein the dispenser adminis-ters a complete pharmaceutical dosage regimen for a prolonged period of time, the use of which dispenser requires intervention only for ini-tiation of the regimen.
The invention can provide a delivery system manufactured as a dispenser comprising a carrier Eor a plurality of tiny pills, wherein the carrier keeps its physical and chemical integrity during its stay in the dispenser and changes its physical and/or chemical integrity on its displacement from the dispenser into a fluid environment of use.
The present invention can provide a drug delivery system that can deliver a beneficial drug housed in a tiny pill contained ~ 3 ~ 3 ln a pharmaeeutical earrier that maintains its .str~eture within the delivery system and changes its strueture on its delivery into the gastrointestinal tract wherein the pharmaceutical carrier dispenses the tiny pill.
The present invention ean provide a drug delivery system eomprising a pharmaeeutical carrier that i.s a dispensable composition for tiny pills, that is innoeuous and whieh carrier on its displacement from the delivery system releases the tiny pills thereby substantially avoiding mammalian tissue irritation and interaetion with mammalian protein tissue.
The presen-t invention ean provide a delivery system eomprising an inner eapsule, whieh eapsule houses at least one of a hydrophilic or a hydrophobie pharmaceutically acceptable carrier comprising tiny pills that contain an insoluble to soluble drug~
and which earrier, when the delivery system is in operation, is pushed substantially intact and substantially unchanged from the delivery system and changes i-ts physical form on displacement from the delivery system for releasing the tiny pills in the environment of use.
The invention can provide a drug delivery device for dispensing a drug to a ruminant, whieh delivery system eomprises an inner lumen containing a nonmeltable and nonaqueous thermo~
plastic composition, a space oeeupying member, and a density member, and which thermoplastic composition comprises tiny pills comprising an insoluble to soluble benefieial agent -that ean be dispensed by the thermoplastie eomposition after said thermo-plastie composition exits the delivery system.

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Other :Eeatures and advantages of the inven-tion will be more apparent to those skilled in the dispensing art from the following detailed description of the specification, taken in conjunction with the drawing figures and the accompanying claims.

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2 In the drawing figures, wh~ch are not drawn to scale but are set 3 forth to illustrate various embodiments of the invention, the drawing 4 figures are as follows:
Figure 1 is a view of a dispenser designed and manufactured for 6 administering a beneficial agent to a warm-blooded animal;
7 Figure 2 is an opened view of the dispenser of Figure 1 through 8 the vertical length of the dispenser for illustrating the structure of 9 the dispenser, wherein the dispenser comprises an internal lumen housing a pharmaceutical1y acceptable carrier that does not melt at 11 the temperature of an animal's body, and which carrier comprises a 12 continuous body member extending through a major length of the lumen 13 with a plurality of tiny pills dispersed therein, and which lumen 14 contains a space occupying member for pushing the continuous carrier from the lumen;
16 Figure 3 is an opened view of the dispenser of Figure 1 taken in 17 conjunction with Figure 2, wherein Figure 3 depicts the dispenser in 18 operation with the carrier formed of a composition that is the~nally 19 stable at the temperature of an animal's environment of use9 said carrier being urged from the lumen as the space occupying member 21 consumes space in the lumen and, concomitantly, urges the continuous 22 carrier from the lumen of the dispenser for releasing tiny pills in 23 the environment of use;
24 Figure 4 is considered with Figure 3, which Figure 4 is seen in opened view depicting a semipermeab1e wall that surrounds a lumen with 26 the dispenser in operation~ wherein the thermally stable carrier 27 severs as it leaves the lumen, enters the environment of use and 28 releases tiny pills, with the main body portion of the carrier still ~ 31~ ARC 1439 1 housed within the lumen of the dispenser;
2 Figure 5 is an opened view of the dispenser depicting a different 3 internal structure configuration comprising a nonmeltable carrier 4 containing tiny pills, a volume consuming member, and a dense member for keeping the dispenser in the rumen of an animal;
6 Figure 6 is an opened view of the dispenser illustrating another7 internal structural arrangement wherein the lumen comprises a carrier8 that is nonmeltable at animal temperature and contains tiny pills, a 9 density member for keeping the dispenser in an environment oF use andpositioned next to the carrier, and means for occupying space in the 11 lumen for pushing the carrier through a mouth in the wall of the 12 dispenser;
13 Figure 7 ls an opened view of the dispenser through the vertical1~ length of the dispenser for illustrating the internal structure of the dispenser comprising an inside wall, an outside wall, a carrier that 16 maintains its physical and chemical integrity inside the dispenser, 17 and means for occupying space in the lumen for urging the carrier with 18 its tiny pills from the dispenser;
19 Figure 8 is an opened view of the dispenser taken in conjunctionwith Figure 7, wherein the dispenser additionally contains a density 21 member for keeping the dispenser in the rumen of an animal;
22 Figure 9 is an opened view of the dispenser illustrating a diffe-23 rent arrangement of the means for housing and transporting tiny pills, 24 means for expanding and occupying space, and the means for keeping the dispenser in the rumen of an animal over time; and~
26 Figure 10 depicts a multiplicity of tiny pills, some in opened 27 section on their release from the supporting matrix carrier of the 28 dispenser.

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1 In the drawing figures and in the specification, like parts in 2 related figures are identified by like numbers. rhe terms appearing 3 earlier in the specification and in the description of the drawing 4 figures, as well as embodiments thereo~, are further described else-where in the disclosure.

7 Turning now to the drawing figures in detail, which are an 8 example of various dispensers provided by the invention, and which g example is not to be construed as limiting, one example of a dispenser is seen in Figures 1 through 9, considered together, and indicated by 11 the numeral 10.
12 In Figure 1 dispenser 10 is seen comprising a body 11 that is 13 adapted, shaped and sized for admittance, such as orally, into the 14 gastrointestinal tract for extended residency in the stomach.
In Figure 2, dispenser 10 is seen in opened section for illustra-16 ting the structure of dispenser 10. Dispenser 10 of Figure 2 com-17 prises body 11, wall 12 and mouth 13. Wal1 12 surrounds internal 18 lumen 14. In a presently preferred embocliment wall 12 comprises, in 19 whole or at least in part, a semipermeable composition that is sub-stantially permeable to the passage of an external fluid present in 21 the environment of use, and it is substantially impermeable to the 22 passage o~ a beneficial agent and other ingredients în lumen 14 of 23 dispenser 10. In another embodimentg wall 12 can comprise a semiper-24 meable composition and, in part, wall 12 can comprise a different composition such as a semipermeable composition and a polyolefin, In 26 its manufacture wall 12 is nontoxic, and it maintains its physical and 27 chemical integrity, that is, wall 12 does not erode during the dispen-28 sing life of dispenser 10.

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1 ~all 12 surrounds and defines an internal lumen 14. Lumen 14 2 contains carrier means 15 comprising tiny pills 16. Lumen 14 contains 3 also driving means 17, also identified as a space or volume consuming 4 means 17, that ls layered and in contact with carrier means 15. Both carrier means 15 and driving means 17 have a shape that corresponds to 6 the internal shape of lumen 14. A passageway 13, also identified for 7 the purpose of this invention as a mouth or opening, connects the 8 outside of dispenser 10 with lumen 14. Passageway 13, that is a wide-9 mouth opening in wall 12, which opening 13 comprises a cross-section that is substantially equal to the internal cross-sectional dimensions 11 of lumen 14. In an optional embodiment, not shown, wall 12 at opening 12 13 can curve slightly inward for assisting in governing the movement 13 of carrier means 15 from lumen 14. Carrier means 15 houses a multi-14 plicity of tiny pills 16 for the controlled delivery of a beneficial agent over time. In Figure 10, tiny pills 16 are seen in detail.
16 Figure 3 depicts dispenser 10 in operation in a biological fluid 17 environment of use. Dispenser 10 in Figure 3 comprises body 11, wall 18 1~, mouth 13, lumen 14, pharmaceutically acceptable carrier means 15, 19 tiny pills 16 dispersed in pharmaceutically acceptable carrier means 15, and space consuming means 17. Pharmaceutically acceptable carrier 21 means 15 keeps its integrity inside lumen 14~ That is, carrier means 22 15 is nonmeltable at the temperature of use, such as an animal's body 23 temperature, it does not erode in the lumen, and it does not disinteg-24 rate, dissolve, decompose or hydrolyze while carrier 15 is inside lumen 14. Space consuming means 17, in operation inside lumen 14, 26 absorbs and imbibes aqueous fluid through wall 12, thereby causing 27 space consuming means 17 to expand and continuously occupy additional 28 space in lumen 14. This occupying of space inside lumen 14 by means ~ 3 ~

2 17 causes means 17 to apply pressure against carrier 15 and urge it through mouth 13. Carrier means 15 thus enters the environment of use at carrier environment interface 18.
Figure 4 depicts carrier means 15 releasing tiny pills 16 into the environment of use at interface 18. In the presence of an aqueous 6 type biological fluid in the environment of use carrier 15 releases 7 tiny pills 16 at a controlled rate by at least one process of erosion9 8 leaching, osmotic bursting or disintegration. In the environment of the gastrointestinal tract carrier 15 bioerodes, disintegrates, dis-solves or hydrolyzes as it enters the environment, thereby continuously 11 presenting a new surface of carrier 15 with tiny pills 16 to the 12 environment. Dispenser 10 delivers tiny pills 16 at a controlled rate 13 by the combined operations of carrier 15 releasing tiny pills 16 and 14 means 17 consuming space in lumen 14 over time.
Figure 5 illustrates dispenser 10 comprising lumen 14 containing 16 a dense member 19. In this embodiment dense member 19, also called 17 densifier, is an important component of dispenser 10 for keeping 18 dispenser 10 in the rumen of an animal over a prolonged period of 19 time. In Figure 5, lumen 14 houses pharmaceutical carrier means 15 in layered contact with a surface of space consuming means 17, whlch 21 lattermeans 17 is in contact with densifier 19.
22 Figure 6 illustrates another embodiment of dispenser 10. In 23 Figure 6, dispenser 10 is seen in opened view with lumen 14 housing 24 pharmaceutically acceptable carrier means 15 in contact with densifier 19. Densifier 19 is in contact with volume consuming means 17. In 26 this embodiment space consuming means 17 is positioned distant from 27 mouth 13. The presence of densifier 19 in dispenser 10 adapts 28 dispenser 10 for use in a rumen. A rumen retentive dispenser 10 can ~ 3 1 ~

be manufactured in a variety of sizes and shapes for releasing tiny pills 16 to a ruminant animal. One presently preferred shape is an elongated~or lengthened space such as a cylinder shape, or a capsule shape, with a wide mouth. For example, for use with sheep dispenser 10 can embrace an elongated shape and have a diameter of 0.5 inches to 1 inch (1.3 cm to 2.5 cm), and a length of 0.5 inches to 4 inches (1.3 cm to 10 cm). For use with cattle dispenser 10 comprises a diameter of 0.5 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).
Figure 7 is an opened view of another embodiment of dispenser 10 11 provided by the invention. In Figure 7 dispenser 10 comprises wall 12 12 that surrounds an internal wide mouth capsule 20. In one presently 13 preferred embodiment comprising internal wide mouth capsule 20, capsule 20 surrounds lumen 14. Lumen 14 contains a nonthermo-responsive carrier 15 containing tiny pills 16. Lumen 14 further contains space 16 consuming means 17 that is in layered contact with a contacting surface-17 o~ carrier means 15. In lumen 14 both carrier means 15 and space 18 consuming means 17 have a shape that corresponds to the internal shape of lumen 14.
Figure 8 is an opened view of another embodiment of dlspenser 10.
21 In ~igure 8 dispenser 10 compr~ses an exterior wall 12 that surrounds 22 interior wall 20. In this manufacture exterior wall 12 and interior 23 wall 20 jointly define internal space 14. Interna1 space 14 contains 24 pharmaceutical carrier means 15 having tiny pills 16 dispersed therein, a density member 19 in contact with carrier means 15 and a 26 space consuming means 17 in contact with density member 19. In this 27 manufacture space consuming means 17 is distant from carrier means 15.
In space lumen 14 carrier means 15, density member 19 and space consuming ~ 3 ~

means 17 all embrace a shape that corresponds to the internal shape of space 14.
Figure 9 is an opened view of another manufacture of dispenser 10.
In Figure 9 space consuming means 17 is in contact with the pharmaceu-tical carrier means 15 and density member 19 is distant from pharma-ceutical carrier 15. In a presently preferred embodiment as space consuming means 17 imbibes fluid and takes up space in lumen 14, it forms within itself an immiscible boundary at the interface defined by means 15 and means 17.
Figure 10 depicts tiny pills 16 in detail. In Figure 10 tiny 11 pills 16 comprise a core of beneficial agent 21, such as a drug, 12 surrounded by a wall 22 of a wal1 forming release rate controlling 13 composition. In one embodiment tiny pills 16 can have wall 22 made 14 from a material that releases beneficial agent 21 in the stomach, or in another embodiment tiny pill 16 can have a wall 22 comprising an 16 enteric composition which prevents release of agent 21 in the stomach, 17 but will release agent 21 in thè intestine. Additionally, the 18 materials comprising wa11 22 can be selected from materials that release agent 21 by different physicalchemical mechanisms. These mechanisms for tiny pill 16 lnclude erosion, diffusion, osmotic 21 bursting, metabolism9 and the like. Wall 22 can have various thick-22 nesses as an additional aid for providing timed release of agent 21.
23 In the drawing figures and in the specification like parts in 24 related figures are identified by like numbers. The terms appearing earlier in the specification and in the description of the drawing 26 figures, as well dS embodiments thereof, are further detailed else-27 where in the disclosure.

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2 In accordance with the practice of this invention it has been 3 found that dispenser 10 can be manufactured with a lumen that houses 4 in a cooperative relationship in the lumen carrier means 15, tiny pills 16, space consuming means 17 and, in other optional embodiments, 6 density member 19. The dispenser 10 is formed by wall 12 comprising a 7 composition that does not adversely affect the carrier9 the beneficial 8 agent, the tiny pills, the space consuming means, the density member 9 and other ingredients such as an osmagent, an osmopolymer, a gas generating couple, and the like, that can be housed in dispenser 10.
11 Wall 12 is permeable, in at least a part9 to the passage of an external 12 fluid such as water and biological fluids and it is substantially 13 impermeable to the passage of beneficial agent, tiny pills9 osmagents, 14 osmopolymers, and the like. The wall comprises a material that does not adversely affect an animal, or host, or the components comprising 16 the dispenser and the selectively semipermeable materials used for 17 forming the wall are nonerodible and they are insoluble in fluids.
18 In one embodiment typical selectively semipermeable materials for 19 forming the wall are cellulose esters, cellulose ethers and cellulose ester-ethers. These cellulosic polymers have a degree of substitu-21 tion, D. S., on the anhydroglucose unit, from greater than O up to 3, 22 inclusive. By degree of substitution is meant the average number of 23 hydroxyl groups originally present on the anhydroglucose unit compri-24 sing the cellulose polymer that are replaced by a substituting group.
Representative compositions include a member selected from the group 26 consisting of cellulose acylate, cellulose diacylate, cellulose 27 triacylate, cellulose acetate, cellulose diacetate, cellulose tri-28 acetate, mono-, di- and tricellulose alkanylates, mono-, di- and ~31~

1 tricellulose aroylates, and the like. Exemplary polymers include 2 cellulose acetate having a D.S. up to 1 and an acetyl content up to 3 21~; cellulose acetate having an acetyl content of 32 to 39.8%;
4 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 6 content of 35 to 44~8~o~ and the like. More specific cellulosic poly-7 mers include cel1ulose propionate having a D~S. of 1~8 and a propyl 8 content of 39.2 to 45% and a hydroxyl content of 2~8 to 5~470; cellu-9 lose 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 11 having an acetyl content of 2 to 29%, a butyryl content of 17 to 53%
12 and a hydroxyl content of 0.5 to 4~7~; cellulose triacylates having a 13 D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, 14 cellulose tripalmitate, cellulose trisuccinate, and cellulose tri-octanoate; cellulose diacylates having a D.S. of 2.2 ~o 2.6 such as 16 cellulose disuccinate, cellulose dipalmltate, cellulose dioctanoate, 17 cellulose dipentanoate, co-esters of cellulose such as cellulose 18 acetate butyrate and cellulose acetate propionate, and the like.
19 Additional polymers include ethyl cellulose o~ various degrees of etherification with ethoxy content oF from 40% to 55%~ acetaldehyde 21 dimethyl cellulose acetate; cellulose acetate ethyl carbamate; cellu 22 lose acetate methyl carbamate; cellulose acetate dimethyl amino 23 acetate; semipermeable polyamides; semipermeable polyurethanes; semi-24 permeable sulfonated polystyrenes; semipermeable cross-linked selec-tive polymers formed by the coprecipitation of a polyanion and a 26 polycation as disclosed in United States Patents Nos. 3,173,876;
27 3,276,586; 3,541,0905; 3,541~006 and 3~546,142; semipermeable poly-28 mers as disclosed by Loeb and Sourirajan in United States Patent No.

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1 3,133,132; semipermeable lightly cross-linked polystyrene derivatives;
semipermeable cross-linked poly(sodium styrene sulfonate); semiper-meable cross-linked poly(vinylbenzyltrimethyl ammonium chloride);
semipermeable polymers exhibiting a fluid permeability of 2.5 X 10 11 to 2.5 X 10 4 (cm2/hr ' atm) expressed per atmosphere of hydrostatic 6 imbibition, or osmotic pressure difference across the semipermeable wall. The polymers are known to the art in United States Patents Nos.
3,845,770; 39916,899 and 4,160,020; and in Handbook of Common Polymers by Scott, J.R. and Roff, W.J. (1971) published by CRC Press, Cleveland, OH~
11 Further, in accordance with the practice of this invention~ it 12 has now been found that internal wall 20 of dispenser 10 can be made 13 as a capsule member. The capsule member generally is tubular shaped 14 and it has a mouth at one end, and at the end distant therefrom it is closed in a hemispherical or dome shaped end. The capsule member 16 serves as a hollow body having a wall 20 that surrounds and defines an -17 interior compartment 14 provided with an opening 13 for establishing 18 communication w~th the exterior of the capsule and ~or filling the 19 capsule.
In one embodiment a capsule is made by dipping a mandrel, such as 21 a stainless steel mandrel, into a batch containing a solution of a 22 capsule wall forming material to coat the mandrel with the material.
23 Then the mandrel is withdrawn, cooled and dried in a current of air.
24 The capsule is stripped from the mandrel and trimmed to yield a cap-sule with an internal lumen. The materials used for ~orming the 26 capsule are the commercially available materials including gelatin, 27 gelatin having a viscosity of 15 to 20 millipoises and a bloom 28 strength up to 150 grams; gelatin having a bloom value of 160 to 250;

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1 a composition comprising gelatin, glycerine water and titanium di-2 oxide; a composition comprising gelatin, erythrosin, iron oxide and 3 titanium dioxide; a composition comprising gelatin, glycerine, sor-4 bitol, postassium sorbate and titanium dioxide; a composition compri-sing gelatin, acacia, glycerin and water; water soluble polymers that 6 permit the transport of water therethrough and can be made into 7 capsules, and the like.
8 Wall 12 also can comprise a flux regulating agent. The flux 9 regulating agent is a compound added to assist in regulating the fluid permeability or flux through the wall 12. The flux regulating agent 11 can be a ~lux enhancing agent or a flux decreasing agent. The agent 12 can be preselected to increase or decrease the liquid flux. Agents 13 that produce a marked increase in permeability to ~luid, such as 14 water, o~ten are essentially hydrophilic~ while those that produce a marked decrease to fluids, such as water, are essentially hydrophobic.
16 The amount of regulator in the wall when incorporated therein 17 generally is from about 0.01% to 20% by weight, or more. The flux 18 regulator agents i~ one embodiment that increase flux include poly-19 hydric alcohols, polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols, and the like. Typical flux enhancers include 21 polyethylene glycol 300, 400~ 600, 1500, 4000, 6000 and the like; low 22 molecular weight glycols such as polypropylene glycol, polybutylene 23 glycol and polyamylene glycol; the polyalkylenediolx such as 24 poly(l,3-propanediol), poly(l,4-butanediol), poly(1,6-hexanediol) and the like; aliphatic dlols such as 1,3-butylene glycol; 1,4-penta-26 methylene glycol; 1,4-hexamethylene glycol, and the like; alkylene 27 triols such as glycerine; 1,2,3,-butanetriol; 1,2,4,-hexanetriol;
28 1,3,6-hexanetriol, and the like; esters such as ethylene glycol 1 3 ~

1 dipropionate; ethylene glycol butyrate; butylene glycol dipropionate;
2 glycerol acetate esters, and the like. Representative fluid decrea-3 sing agents include phthalates substituted with an alkyl, an alkoxy or 4 with both an alkyl and alkoxy groups such as diethyl phthalate, di-methoxyethyl phthalate, dimethyl phthalate and ~dl(2-ethyl-hexyl)-6 alkyl phthalate], aryl phthalates such as triphenyl phthalate and 7 butyl benzyl phthalate; insoluble salts such as calcium sulphate, 8 barium sulphate, calcium phosphate and the like; insoluble oxides g such as titanium oxide; polymers in powder, granule and like forms such as polystyrene, polymethylmethacrylate, polycarbonate and polysul-11 fone; esters such as citric acid esters esterfied with long chain 12 alkyl groups; inert and substantially water impermeable fillers;
13 resins compatible with cellulose based wall forming materials and the 14 like.
Other materials that can be used to form the wall 12 for impairing 16 flexibility and elongation properties to the wall, for making wall 12 17 less-to-nonbrittle and to render tear strength, include phthalate 18 plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl 19 octyl phthalate, straight chain phthalates of six to eleven carbons, di-isononyl phthalate, di-isodecyl phthalate, and the like. The 21 plasticizers include nonphthalates such as triacetin, dioctyl azelate, 22 epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl tri 23 mellitate, sucrose acetate isobutyrate, epoxidized soybean oil and the 24 like. The amount of plasticizer in a wall when incorporated therein is about 0.01% to 20~D by weight, or higher.
26 Representative of means 17 for manu~acturing space consuming 27 means 17 for urging pharmaceutically carrier means 15 from lumen 14 28 through mou-th 13 are at least one of a member selected from the group 131~7~ ARC 1439 1 consisting of an osmopolymer, an osmagent and a gas generating couple.
2 Exemplary of an osmopolymer that can be used for the present purpose 3 is a hydrogel. The hydrogel ln the dispenser comprises a shape that 4 corresponds to the internal shape of lumen 14. The hydrogel composi-tion is noncross-linked or, optionally, cross-linked and it possesses 6 osmotic properties such as the ability to imbibe an exterior fluid 7 through semipermeable wall 12 and exhibits an osmotic pressure gra-8 dient across semipermeable wall 12 against a fluid outside dispenser g system 10. The materials used for forming the space consuming member that are swellable and expandable are polymeric materials neat and, 11 optionally, polymeric materials blended with osmotic agents tha~
12 interact wlth water or biological fluid, absorb the fluid and swell or 13 expand to an equilibrium state. The polymer exhibits the ability to 14 retain a significant fraction of imbibed fluid in the polymer molec-ular structure. The polymers in a preferred embodiment are gel poly-16 mers that can swell or expand to a very high degree, usually exhibi-17 ting a 2 to 50 fold volume increase. The swellable9 hydrophilic 18 polymers, also known as osmopolymers can be noncross-linked or lightly l9 cross-linked. The cross-links can be covalent or ionic bonds with the polymer possessing the ability to swell in the presence of fluid, and 21 when cross-linked it will not be dissolved in the fluid. The polymer 22 can be of plant, animal or synthetic origin~ Polymeric materials 23 useful for the present purpose include poly(hydroxyalkylmethacrylate) 24 having a molecular weight of from 5,000 to 5,000,000; poly(vinyl-pyrrolidone) having a molecular weight of from lO,000 to 360,000;
26 anionic and cationic hydrogels; poly(electrolyte) complexes;
27 poly(vinylalcohol) having a low acetate residual; a swellable mixture 28 of agar and carboxymethyl cellulose; a swellable composition compri-~ 3 ~

1 sing methyl cellulose mixed with a sparingly cross-linked agar; a 2 polyether having a molecular weight of from 10,000 to 6,000,000;
3 water swe!lable copolymer produced by a dispersion of finely divided 4 copolymer of maleic anhydride with styrene, ethylene, propylene, or isobutylene; water swellable polymer of N-vinyl lactams; and the like.
6 Other gelable, fluid imbibing and retaining polymers useful such 7 for forming the hydrophilic, expandable push member 17 include pectin 8 having a molecular weight ranging from 30,000 to 300,000; poly-g saccharides such as agar, acacia~ karaya, tragacanth, algins and guar;
Carbopol~, an acrylic acid polymer? a carboxyvinyl polymer, sometimes 11 referred to as carboxypolymethylene, a polymer of acrylic acid cross-12 linked with a polyallyl ether of succrose~ as described in U. S. Pats.
13 Nos. 2,798,053 and 2,909,462 and available as Carbopols~ 9349 940 and a 941, and its salt derivatives; polyacrylamides; water-swellable indene maleic anhydride polymers; Good-rite~ polyacrylic acid having 16 a molecular weight of 80,000 to 200,000; Polyox~ polyethylene oxide 17 polymers having a molecular weîght of 100,000 to 5,000,000; starch 18 graft copolymers; Aqua-Keep~ acrylate polymers with water absorb-19 abili~y of about 400 times its original weight; diesters of poly-glucan; a mixture of cross-linked polyvinyl alcohol and poly(N-vinyl-21 2-pyrrolidone); zein available as prolamine; poly(ethylene glycol) 22 having a molecular weight of 4,000 to 100,000, and the like. In a 23 preferred embodiment, the expandable member is formed from polymers 24 and polymeric compositions that are thermoformable. Representative polymers possessing hydrophilic properties are known in United States 26 Patents Nos. 3,865,108; 4,002~173; 4,207,893; 4,327,725, and in 27 Handbook of Common Polymers, by Scott and Roff, published by Cleveland 28 Rubber Company, Cleveland, OH.

1 The osmagent that can be used for the purpose of providing space 2 consuming means 17 comprise inorganic and organic compounds that 3 exhibit an osmotic pressure gradient against an external fluid across 4 semipermeable wall 12. Osmagents are also known as osmotically effec-tive compounds and as osmotically effective solutes. The osmagent 6 imbibes fluid from the outside of dispenser 10 into lumen 14 causing 7 it to produce a solution or a suspension that continuously occupies 8 more space in lumen 14. As more fluid is imbibed into lumen 14~ it g exerts a pressure against pharmaceutically acceptable carrier 15 pushing it from dispenser lO. Osmotically effective compounds useful 11 for the present purpose include inorganic and organic salts, poly-12 saccharides, carbohydrates, and the like. Representative solutes 13 include magnesium sulfate, magnesium chloride, sodium chloride, potas-14 sium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfate, lithium sulfate, sodium sulfate, potassium acid phos-16 phate, calcium lactate, tartaric acid, lactose, fructose, mannitol, 17 sorbitol, and mixtures thereof. The osmotically active compound is 18 initially present in lumen 14 in excess and it can be in particle, 19 crystal, pellet, powder or granule form. The osmotic pressure of an osmotic compound can be measured with a commercially available 21 osmometer identified as Vapor Pressure Osmometer, Model 2~, available 22 from Hewlett-Packard, Avondale, PA.~ other osmometers such as the 23 Knauer Vapour Pressure Osmometer can be used for the present purpose.
24 The osmotic pressure in atmospheres, atm, of osmagents suitable for this invention will be greater thar zero atm, generally from zero atm 26 up to 500 atm, or higher.
27 The osmotically effective compound that can be blended homo-2~ geneously or heterogeneously with the swellable polymer, to form a ~ ARC 1439 1 push member 17, are the osmotically effective solutes that are soluble 2 in fluid, imbibed into the swellable polymer, and exhibit an osmotic 3 pressure gradient across the semipermeable wall against an exterior 4 fluid. Osmotically effective osmagents useful for the present purpose include magnesium sulfate, magnesium chloride, sodium chloride, 6 lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, 7 sorbitol, inositol, succrose, glucose, and the like. The osmotic 8 pressure in atmospheres, atm, of the osmagents suitable for the inven-9 tion will be greater than zero atm, generally from greater than zero atm up to 500 atm, or higher. The swellable, expandable polymer, in 11 addition to providing a driving source 17 for urging carrier 15 con-12 taining beneficial tiny pills 16 from dispenser 10, further serves to 13 function as a supporting matrix for an osmotically effective solute.
14 The osmotic solute can be homogeneously or heterogeneously blended with the polymer to yield the desired expandable member 17. The 16 composition in a presently preferred embodiment comprises at least one 17 polymer and at least one osmotic solute. Generally, a composition 18 will comprise about 20% to 90% by weight of polymer and 80% to 10%
19 ~eight of osmotic solute, with a presently preferred composition comprising 35% to 75% by weight of polymer and 65% to 25% by weight of 21 osmotic solute.
22 The gas generating couple operable as space occupying means 17 23 is, in a presently preferred embodiment, an effervescent couple or 24 composition. The gas generating couple comprises at least one prefer-ably solid acidic material and preferably solid basic material that 26 dissolve and react in aqueous fluid that enters the dispenser to 27 produce carbon dioxide. The gaseous generation of carbon dioxide 2~ leads to the volume displacement of carrier 15 containing beneficial ~ e~ 9 ~ ~ ARC 1439 1 agent 17 from dispenser 10. The gas generating couple can be present 2 in powder, crystalline, granular, compressed forms, and the like. The 3 acidic or acids that can be used include organic acids such as malic, 4 fumaric, tartaric, itaconic, maleic, citric, adipic, succinic and mesaconic, and the corresponding anhydride such as itaconic anhydride, 6 and citriconic anhydride. Also, inorganic acids such as sulfamic or 7 phosphoric, and the like, can be used for gas generation. Acid salts 8 such as the sal~s of organic foods can be used including monosodium g citrate, potassium acid tartarate, and potassium bitartrate. The basic compounds include metal carbonate and bicarbonate slats such as 11 alkali metal carbonates and bicarbonates, or alkaline earth carbonates 12 and bicarbonates, Exemplary materials include the alkali metals 13 lithium, sodium, potassium carbonate and bicarbonate, and the alkaline 14 earth compounds magnesium and calcium carbonate or bicarbonate. Also useful are ammonium carbonate, ammonium bicarbonate and ammonium 16 sesquecarbonate. The combination of certain of these acids and bases 17 results in a more rapid gas production or effervescence when contacted 18 by water. In particular, either citric acid or a mixture of citric 19 acid and tartaric acid and sodium bicarbonate give a rapid gaseous reaction that can be used ~or urging carrier 17 from dispenser 10.
21 I-t will be understood the amount of acidic and basic materials in a 22 couple can vary over a wide range to satisfy the amount of gas genera-23 tion need to urge carrier 17 form dispenser 10. The essentially 24 anhydrous or dry couple is preferably substantially stoichiometrically balanced to produce a combination that generates carbon dioxide.
26 Also, the acid and base materials can be used in any convenient pro-27 portion between 1 to 200 parts and 200 to 1 part on a weight basis to 2~ produce the desired results. In additionl the gas generating material 1 3 ~

l can be a substance that generates gas on contact with water such as 2 calcium carbide and carbure.
3 Pharmaceutically acceptable carrier means 15 in a presently 4 preferred embodiment maintains its physical and chemical integrity inside lumen 14 of dispenser 10. The phrase "maintains its physical 6 and chemical integrity inside lumen 14", used for the purpose of this 7 invention, denotes a carrier formulation that does not substantially 8 undergo change in lumen 14 of dispenser 10. That is, carrier formula-9 tion 15 does not hydrolyze, erode, disintegrate or dissolve in lumen 14 during operation of dispenser 10. The expression "nonmeltable", as 11 used for the purpose of this invention means carrier means 15 sub-12 stantially does not melt inside lumen 14 of dispenser 10. That is, 13 carrier means 15 inside lumen 14 substantially does not change from a 14 solid to a liquid state in lumen 14. Carrier formulation 15, on its delivery from dispenser 10 can, in a fluid biological environment of 16 use such as the gastrointestinal tract ol` a warm-blooded animal, 17 undergo hydrolysis in the acidic or basic pH of the tract, it can 18 undergo surface erosion, disintegration, dissolution, be hydrolyzed by 19 enzymes, digested by bacteria or fungi, and the like.
Exemplary of carrier formulation means 15 generically 21 includes a member selected from the group consisting of a polyester, 22 polylactide, polyacetal, polyorthoester, polyorthocarbonate, and the 23 like. Representative of more specific carrier formulatlons 15 24 includes a member selected form the group consisting of polyglycolic acid exhibiting a Tm of 230C, wherein Tm is the melting point, 26 polydiglycolide having a Tm of 230C, polylactic acid having a Tm of 27 180C, polydimethylglycoloic acid with a Tm of 240C, poly 23 carprolactone having a Tm of 63C, polyalkylene adipate wherein the 13~9~7~

1 alkylene group comprises 10 carbons having a Tm of 77C, polylactide-2 glycolide, and the like.
3 Representative of additional compositions for forming 4 carrier means 15 comprise polyanhydrides, polyanhydride polymers of sebacic and azelaic acid, hydrophobic polycarbolyic acids having one 6 ionizable carboxylic hydrogen for each 8 to 22 total carbon atoms, 7 bioerodible polymers that innocuously disintegrate or breakdown as a 8 unit structure on release by dispenser 10 such as a hydrophobic g polycarboxylic acid having a repeating backbone unit of ~ to 22 carbon atoms for each pendant carboxylic hydrogen; a bioerodible polyvalent 11 ion cross-linked polyelectrolyte with a polyvalent ion selected frcm 12 the group consisting of aluminum, barium, cadmium, calcium, copper, 13 iron, and zinc with the po1yelectrolyte selected for the group consis-14 ting carrageenan, pectic acid, pectinic acid and the like; a polyes~
ter of the formula ~-0-W-CO]y wherein W is an alkylene of 1 to 4 16 carbons and y is a whole number to provide a polymer having a molecular 17 weight of 4,0~0 to 100,000; a polyorthoester selected fro~ the group 18 consisting of poly(2,2-dioxo trans-1,4-cyclohexane dimethylene 19 tetrahydrofuran), poly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran), poly(1,4-cyclohexane dicarb1nyl-2,2-dioxotetrahydrofuran), poly (2,2-21 dioxohexamthylene-1,3-dioxolane), poly(2,2-dioxa-trans-2-methyl-22 cyclohexane-1.4-diethylene-2-pyrrolidone), poly(2,2-dioxa-cis, trans-23 1,4-cyclohexane-dimethylene-2-thiocane), and the like. Representative 24 of additional compositions for forming carrier means 15 include poly-amino acid, polypepetide, polyglutamate, polyglutamic acid, po1yly-26 sine, and the like.
27 Representative of additional polymeric materials for 28 providing carrier means 15 are a hydrophilic polymer selected form the -26~

~3 ~ ~71 ARC 1439 1 group, consisting of a poly(alginate), poly(carrageenan), poly(guar 2 gum), poly(gum agar), poly(gum arabic), poly(gum ghatti), poly(gum 3 paraya), poly(gum tragacanth), poly(tamarid gum), poly(xanthan gum) 4 and the like. The hydrophilic polymeric material, when used for carrier means 15, comprises a different polymeric composition when a 6 hydrophilic polymeric material is used for space consuming member 17, 7 or when carrier means 17 and space consuming means 17 are in contact 8 with each other, g Carrier means 15, in additional operative embodiments, can be manufactured by (1) compressing water insoluble materials into a 11 shape that corresponds to the internal shape of lumen 14. For example, 12 carrier means 15 can comprise a tableted, an elongated stick-like 13 shape or the like. Carrier means 15, in its additional operative 14 embodiments, maintains its integrity in lumen 14, and on its exit ~rom dispenser 10 disintegrates9 or the like, in the fluid environment of 16 use. In this manufacture, carrier means 15 can comprise polymerized 17 particulate composition of matter comprising polyethylene, polyprophy-18 lene, cellulose acetate, ethylcellulose, polysulfone, cellulose acetate 19 butyrate, micro-crystalline cellulose, and the like.
Carrier means 15, in another embodiment, can be manufactured 21 from (2) substantially insoluble organic and inorganic substances.
22 Carrier 15, in this embodiment, keeps its shape ;n lumen 1~, but loses 23 its shape in an environment of use. Representative of insoluble 24 organic and insoluble solids used for this purpose comprise a member selected from the group consisting essentially of calcium carbonate, 26 calcium sulfate, diatomaceous earth, clay, silicon dioxide, pulverized 27 glass, and the like.
28 A carrier means 15, with operative properties can be manu-~3~9~ ARC 1439 1 facture in one embodiment, with good properties for engaging in con-2 tacting relation wall 12 or wall 20, by compounding a member selected 3 from group (1) with a member selected from group (2). For example, 4 materials selected from (l) and (2) are mixed with each other and with a lubricant or an oil and then with a small quantity of a member 6 selected from the group consisting of a swellable polymer such as7 gelatin, pectin, and the like, and with an optional disintegrating 8 agent such as solka floc, and the like. The presence of the dis-g integrating agent in carrier means 15 on carrier means 15's exposure to the environment of use results in the break-up of the carrier into 11 smaller parts with the concurrent release of tiny pills 16 into the 12 environment of use.
13 Tiny pills 16 comprise a wall composition 22 that surrounds 14 a beneficial agent 21. Wall 22 of tiny pills 16 in one embodimentconsists essentially of a fatty ester mixed with a wax. The fatty 16 ester comprises a member such as a triglyceryl ester selected from the 17 group consisting of glyceryl distearate, glyceryl tristearate, glyceryl 18 monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl 19 monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaprate, glyceryl dicaparate, glyceryl 21 tricaparate, glyceryl monomyristate, glyceryl dimyristate, glyceryl 22 trimyristate, glyceryl monodecenoate, glyceryl didecenoate and 23 glyceryl tridecenoate.
24 The wax included in the wall forming composition comprises a member selected from the group consisting essentially of beeswax, 26 cetyl palmitate, spermacetic wax, caranuba wax, cetyl myristate, cetyl 27 palmitate, ceryl cerotate, stearyl palmitate, stearyl myristate, and 28 lauryl laurate.

'~

1 The composition comprising the ester and the wax can be 2 coated around the drug by using an organic solvent such as a member 3 selected from the group consisting of carbon tetrachloride, chloro-4 form, trichloroethylene, ether, benzene7 ethyl acetate, methyl ethyl ketone, isopropyl alcohol, and the like. The fatty esters, waxes, 6 solvents and procedures for making tiny pills that slowly disintegrate 7 and continuously provide drug over a period of 10 to 12 hours are 8 disclosed in United States Patent No. 2,793,979.
g Wall 22 of tiny pills 16 in another embodimen-t comprises an osmotic wall ~orming material that releases drug 21 at a controlled 11 rate by the process of osmotic bursting over time. Drug 21 in this 12 embodiment is present in the form of an osmotic solute, such as a 13 therapeutically acceptable salt3 and it exhibits an osmotic pressure 14 gradient across wall 22 against an external fluid. The membrane material used to form wall 22 are those per~eable to the passage of an 16 external fluid and substantially impermeable to the passage of drug.
17 Typical materials include a member selected furm the group consisting 18 of cellulose acylate, cellulose diacylate, cellulose triacylate, 19 cellulose acetate, cellulose diacetate, cellulose triacetate, cellu-lose acetate having a degree of substitution, D.S., up to 1 and an 21 acetyl content of 21%; cellulose diacetate having a D.S. of 1 to 2 22 and an acetyl content of 21 to 35~0; cellulose triacetate having a 23 D.S. of 2 to 3 and an acetyl content of 35 to 44.870; cellulose acetyl 24 propionate, cellulose acetate butyrate, and khe like. The osmotic wall can be coated around the drug in varying thickness by pan coating, 26 spray-pan coating, Wurster~ fluid air-suspension coating and the like.
27 The wall 22 is formed using organic solvents, including those mentioned 28 above, and solvent systems such as methylene chloride-methanol, ~3~9~7~

1 methylene chloride-acetone, methanol-acetone, ethylene dichloride-2 acetone, and the like. Osmotic wall forming material, procedures for 3 forming the wall, and osmotic bursting procedures are disclosed in 4 United States Pat. Nos. 2,799,241; 3,952,741; 4,014,334 and 4,016,880.
6 Wall 22 of tiny pill 16 in another embodiment can comprise a 7 drug release rate controlling material. That is, in one embodiment 8 drug 21 dissolves in the wall and passes though wall 22 at a controlled g rate over time. Exemplary materials useful for forming a drug release rate controlling wall include ethylene-vinyl acetate, ethyl cellulose, 11 polyethylene, cross-linked polyvinyl pyrrolidone, vinylidene chloride-12 acrylonitrile copolymer, polypropylene, silicone, and the like. The 13 wall can be applied by the techniques described above, and materials 14 suitable for forming wall 22 are described in United States Pa. Nos.
3,938,515; 3,948,262; and 4,014,335.
16 Wall 22 of tiny pill 16 in still another embodiment can comprise 17 a bioerodible material that bioerodes at a controlled rate and re-18 leases drug 21 to the biological environment of sue. Bioerodible 19 materials useful for ~orming wall 22 include polyvalent acid or alkali mobile cross linked polyelectrolytes, polycarboxy1ic acid, polyesters, 21 polyamides, polyimides, polylactic acid, polyglyco1ic acid, poly-22 orthoesters, and polyorthocarbonates. The polymers and procedures for 23 forming wall 22 are disclosed in United States Pat. Nos. 3,811,444;
24 3,867,519; 3,888,975; 3,971,367; 3,993,05i and 4,138,344.
The expression '~active agent 21", as used herein~ includes 26 any beneficial agent, or beneficial compound, that can be delivered 27 from the dispenser to produce a beneficial and useful resùlt. The 28 agent can be insoluble to very soluble in the pharmaceutically ~3~9~

1 acceptable carrier 15. The term "active agent", includes alyicide, 2 antioxidant, air purifier, biocide, bactericide, catalyst, chemical 3 reactant, fungicide, fermentation agent, fertility inhibitor, fertility 4 promoter, germicide, plant growth promoter, plant growth inhibitor, preservative, rodenticide, sterili~ation agent, sex sterilant, and the 6 like.
7 In the specification and the accompanying claims, the term 8 "beneficial agent", also includes drug. The term "drug" includes any g physiologically or pharmacologically active substance that produces a local or systemic effect in animals, including warm blooded mammals;
11 humans and primates; avians; household, sport and farm animals;
12 laboratory animals; fishes; reptiles and zoo animals. The term 13 "physiologically" as used herein, denotes the administration of a drug 14 to produce gPnerally normal levels and functions. The term "pharmacologically" denotes generally variations in response to the 16 amount of drug administered to the host. See Stedman's Medical 17 Dictionary, 1966, published by Williams and Wilkins, Baltimore, MD.
18 The active drug that can be delivered includes inorganic and l9 organic compounds without llmitation, including drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, 21 nervous system, skeletal muscles, cardiovascular system, smooth 22 muscles, blood circulatory system, synaptic sites, neuroef~ector 23 junctional sites, endocrine system9 hormone systems, immunological 24 system~ reproductive system, skeletal system, autacoid systems, 2~ alimentary and excretory systems, inhibitory of autocoid systems, 26 alimentary and excretory systems, inhibitory of autocoids and 27 histamine systems. The active drug that can be delivered for acting 2~ on these recipients include anticonvulsants, analgesics, antiParkinsons, ~3~9~

1 anti-inflammatories, calcium antagonists, anesthetics, antimicrobials, 2 antima1arials, antiparasites, antihypertensives, antihistamines, anti-3 pyretics, alpha-adrenergic agnoist, alpha-blockers, biocides, bacteri-4 cides, bronchial dilators, beta-adrenergic blocking drugs, contracep-tives, cardiovascular drugs, calcium channel inhibitors, depressants, 6 diagnostics, diuretics, electrolytes, hypnotics, hormonals, hypergly-7 cemics, muscle contractants, muscle relaxants, opthalmics, psychic 8 energizers, parasympathomimetics, sedatives, sympathomimetics, tran-g quilizers, urinary tract drugs, vaginal drugs, vitamins, nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes, polypeptide 11 drugs, and the like.
12 Exemplary drugs that are very soluble in water and can be 13 delivered by the dispenser of this invention include prochlorperazine 14 edisylate, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine 16 sulfate, benzphetamine hydrochloride, isoproteronol sulfate, metham-17 phetamine hydrochloride, phenmetrazine hydrochloride, bethanechol 18 chloride, methancholine chloride, pilocarpine hydrochloride, atropine 19 sulfate, scopolamine bromide, isoprpoamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, 21 cimetidine hydrochloride, theophylline cholinate, cephalexin hydro-22 chloride, and the like.
23 Exemplary drugs that are poorly soluble in water and that can be 24 delivered by the dispenser of this invention include diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxyben7amine, 26 thiethylperazine maleate, anisindone, diphenadione erythrityl tetrantrate, 27 digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethia-28 zide, chlorpropamide, tolazimide, chlormadione acetate, phenaglycodol, ~ 7 ~ ARC 143g 1 allupurinol, aluminum aspirin, methotrexate, acetyl sul~isoxazole, 2 erythromycin, progestins, esterogenic, progestational, corticosteroids, 3 hydrocort7sone, dydrocortiocosterone acetate, cortisone acetate, triamcinolone, methyltesterone, 17 beta-estradiol, ethinyl estradiol, ethyl estradiol 3-methyl ether, pednisolone, 17 beta hydroxyprogesterone 6 acetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone, 7 norethiederone, progesterone, norgesterone, norethynodrel, and the like.
8 Examples of other drugs that can be delivered by the dispenser g include, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, 11 alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropromazine, 12 methyldopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of alpha-methyldopa hydrochloride, theophylline, calcium glucaonate, ketoprofen, 14 ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, Yincamine, diazepam, phenoxybenzamine, diltia2em, milrinone, 16 captopril, madol, quanbenz, hydrochlorothiazide, ranitidine, flurbi-17 profen, fenbufen~ ~luprofen, tolmetln, alolofenac, mefenamic, flufenamic, 18 difuninal, nimodipine~ nitrendipine, nisoldipine, nicardipine, felodi 19 pine, lido~lazine, tiapamil, gallopamil amlodipine, mioflazine, lisi-nopril, enalapril, captopril, ramipril, end1apriat, famotidine, 21 nizatidine, sucralfate, etintidine, tertatolol, minoxidil, chlor-22 diazepoxide, chlordiazepoxide hydrochloride, diazepam, amitriptylin 23 hydrochloride, i~pramine hydrochloride, imipramine pamoate, and the 24 like~ The beneficial drugs are known to the art in Pharmaceutical Sciences, 14th Ed., edited by Remington, (1979~, published by Mack 26 publishing Co.~ Easton, PA.; The Drug, The Nurse, The Patient, 27 Including Current Drug Handbook, by Falconer, et al.3 (1974-1976) 28 published by Saunder Company, Philadelphia, PA; Medicinal_Chemistry, ~3191D71 1 3rd Ed., Vol 1 and 2, by Burger, published by Wiley-Interscience~ New 2 York; and in Physicians'_Desk Reference, 38th Ed., (1984) published 3 by Medical Economics Co., Oradell~ NJ.
4 The drug in the tiny pills can be in various forms, such as uncharged molecules, molecu1ar complexes, pharmacologically acceptable 6 salts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, 7 phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and 8 salicylate. For acidic drugs, salts of metals, amines or organic g cations; for example, quarternary ammonium can be used. Derivatives of drugs such as ester, ethers and amides can be used. A1SOJ a drug 11 that is water insoluble can be used in a form that is water soluble 12 derivative thereof to serve as a solute, and on its release from the 13 device, is converted by enzymes, hydrolyzed by pH or other metabolic 14 processes to the original biologically active form. The total amount of beneficial agent number of tiny pills in a dispenser generally is 16 about from 0.05 ng to 10 9 or more, with 1ndividual dispenser housed 17 in tiny pills containing, for example, 25 ng, 1 mg 5 mg, IO mg, 25 mg, 18 125 mg~ 250 mg, 500 mg, 750 mg, 1.0 9, 1.2 9, 1.5 9, 4.5 g, 7.5 9, 19 and the like, for administcring to a human.
The term "beneficial agent", as used herein, also comprises 21 medicines or drugs, nutrien~s, vitamins, food supplements and other 22 agents that are administered to farm animals. The dispenser can house 23 various amounts of beneficial agents for administering to a farm 24 animal, which include beneficial agents such as chlortetracycline, ampicillins, penicillins, cephalosporins, and the like; sulfa drugs 26 such as sulfamethazine, sulfathizole, sulfonamiedes 9 and the like;
27 macrolides such as erythromycin, spiramycin, tylosin, and the like;
28 nitrofurans; antibiotics; ionophores such as lasalocid, salinomycin, ~3~7~ ARC 1439 1 virginamycin, and the like; growth-stimulants such as Monesin~ sodium, 2 and Elfazepam~; defleaing agents such as dexamthazone and fluemthazone;
3 rumen fermentation manipulators; antibloat agents such as organo-4 polysiloxanes; growth promoting agents; m~nerals, mineral salts and trace elements formulations such as magnesium, copper, cobalt, iron, 6 manganese, molybdenum, zinc, selenium, copper oxide, copper sulfate, 7 cobalt salt, copper salt, selenium salt, selenium disulfied, sodium 8 selenite; inorganic and organic compounds; cobalt oxide, and the g llke; hormone growth supplements such as stilbestrol; growth efficiency factors, beta-agonist such as denbuterol; vaccines such as 11 bovine diarrhea vaccine; vitamins such as vitamin A, B group, C, D, 12 E, K, and the like; antienteritis agents such as furazolidone;
13 nutritional supplements such as lysine, lysine monhydrochloride, 14 methionine, mexhionine slats, amino acids, peptides, and the like;
beneficial alpha agonists, and the like.
16 Pharmaceutically acceptable carrier means 15 on leaving 17 lumen 1~ of dispenser 10 delivers a beneficial agent 21 in tiny pills 18 1~ to a gastrointestinal tract by rate controlled kinetics. For 19 example, the pharmaoeutical carrier means 15 can release tiny pills 16 by rate controlled di~fusion, by osmosis, by osmotic bursting~ by 21 solution leaching, by solubilization by cross-link cleavage, by 22 solubilization of carrier means 15 by hydrolysis, by solubilization of 23 carrier means 15 by ionizatlon of pendant groups, or by solubilization 24 of carrier means 15 by protonation of pendant groups, by solubiliza-tion by backbone cleavage. The usual amount of beneficial agent 21 in 26 tiny pills for farm animals is from 75 ng to 50 9, for example, 75 ng, 27 1 mg, 5 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1.5 mg, 2 9, 5 9, 10 9, 2~ 25 g, and the like~ A single dispenser can be administered to a farm ~ 3 1 9 a 7 1 ARC 1439 1 animal, for example to a ruminant during a therapeutic program.
2 Dispensers can be provided that have a rate of release from 5 micro-3 grams to 5 grams per day, or higher, for a farm animal.
4 Representative of beneficial medicaments that can be dispensed to a farm animal using the deliver system 10 of this invention include 6 anthelmintics such as benzimidazole, mebendazole, levamisole, albendazole,7 cambendazole, fenbendazole, parbendazole, oxfendazole, osybnedazole, 8 thiabendazole, tichlorfon, praziquantel, thiphanate, morantel, morantel 9 tartrate, pyrantel, pyrantel tartrate, methoprene, and the like;
antiparasitic agents for the management of endoparasites and ectopara-11 sites, such as avermectin and ivermectln, as disclosed in United 12 States Patents No. 49199,569 and 4,389,397 both assigned to Merck &
13 Co., and in Scierce, Vol. 221, pp 823-828, (1983), where in 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 infesta1tions such as grub, liceS
18 mange mite; mite, ticks, larvae, 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 mtcrograms per kilogram 21 per day (5 micro/kg/d), to 250 milligrams per day 250 milligrams per 22 day (250 mg/kg/d), to cattle for establishing avermectin, including 23 ivermectin, blood levels; antimicrobial agents such as chloretetra-24 cycline, oxytetracycline, tetracycline, streptomycin, dihydrostrepto-mycin, bacitracins, erythomycin, by biodegradation, bioerosion, enzy-26 matic action, by oxidation, by reduction, by proteolysis, 27 by displacement, by dissolution, by disintegration and the like.
28 The density member 19, also referred to as densifier 19, 1~31~7~ ARC 1439 1 used in dispenser 10 is dense enough to retain dispenser 10 in the 2 rumen-reticular sac of a ruminant. Density member 19 lets dispenser 3 10 remain in the rumen over a prolonged period of time rather than 4 letting it passing into the alimentary tract and be eliminated therefrom.
As system 10 re~ains in the rumen, tiny pills 16 are delivered by 6 system 10 at a controlled rate to the ruminant over time. Generally, 7 dense member 19 will have a density of from about 0.8 to 8 or higher, 8 with the density in a presently preferred embodiment exhibiting a g specific gravity of from 1.2 to 7.6. For the ruminants, cattle and sheep, it is presently preferred dense member 19 exhibit a density 11 such that there is a resulting system density of about 3 gm/mlO
12 Materials that have a density that can be used for forming dense 13 member 19 include iron, iron shot, iron shot coated with iron oxide, 14 iron shot magnesium alloy, steel, stainless steel, copper oxide, a mixture of cobalt oxide and iron powder, and the like. Dense member 16 19 in delivery system 10 can embrace different embodiments. For 17 example, dense member 19 can be machined or cast as a single, solid 18 piece made of stainless steel having a density of 7.6 gm/ml. The 19 solid member is made having a curved shape that corresponds to the internal shape of system 1~. 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. Density member 19 is described above cons~-sts of means 24 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 27 the exterior surface of a dispenser alone or in laminar arrangement by 28 molding, air spraying, dipping or brushing with a semipermeable wall ~319~7~ ARC 1439 l 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 form a semipermeable capsule laminated wall. The air suspension g procedure is described in United States Patent No. 2j799,241; J. Am.
Pharm. Assoc., Yol. 48, pp 451-459, (1979); and ibid, Vol, 49, pp 82-11 84, (1960). Other standard manufacturing procedures are described in 12 Modern Plastics Encyclopedia, Vol. 46, pp 62-70 (1969); and in 13 Pharmaceutical Sciences, by Remington, 14th Edition9 pp 1626-1678, 14 1970, published by Mack Publishing Co., Easton, PA. In those manu-lS factures wherein the wall is coated by air suspension or by pan 16 coating techniques, mouth 13 is formed in the wall by one of a number 17 of techniques such as laser cutting, m111ing, sawing, drilling and the 18 like, wherein the dev1ce or the mouth-cutting tool is in motion or is 19 stationary.
Exemplary solvents suitable for manufacturing the wall 12 21 include inert inorganic and organic solvents that do not adversely 22 harm the materials, the capsule wall, the beneficial agent, the 23 carrier composition, the expandable member, the dense member, and the 24 final dispenser. The solvents broadly include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, 26 ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatics, 27 aromatics, heterocyclic solvents and mixtures thereof. Typical sol-28 vents include acetone, diacetone alcohol, methanol, ethanol, isopropyl 131907~ ARC 1439 1 alcohol, butyl alcohol, methyl isobutyl ketone, methyl propyl ketone, 2 n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol 3 monoethyl acetate, methylene dichloride, ethylene dichloride, propylene 4 dichloride, carbon tetrachloride, nitroethane, nitropropane, tetra-ch10riethane, ethyl ether, isopropyl ether, cyclohexane, cyclo-octane, 6 benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, 7 water9 and mixtures thereof such as acetone and water, acetone and 8 methanol, acetone and ethyl alcohol, methylene dichloride and methanol, g and ethylene dichloride and methanol.
DESCRIPTION OF EXAMPLES OF THE INVENTION
11 The following examples are merely illustrat1ve of the 12 present invention and they should not be considered as limiting the 13 scope of the invention in any way, as these examples and other equiva-14 lents thereof will become apparent to those versed in the art in the light of the present disclosure, the drawings and the accompanying 16 claims.

18 A dispenser comprising tiny pills of a sympathomimetic drug 19 is prepared as follows: first, powdered drug is mixed with sucrose and the blend passed through a 20 mesh scre~n to produce a multiplicity of 21 cores of drugO Then, a wall-forming composition comprising 85% glycerol 22 monostearate and 15% beeswax in warm carbon tertrachloride is sprayed 23 around the cores in a revolving coating pan until a wall is formed 24 that individually surrounds the cores. Next the solvent is stripped from the tiny pills and the pills dried in a moving air stream.
26 Next, 190 g of poly(2,2-dioxo-trans-1,4-cyclohexane dimethy-27 lene tetrahydrofuran) is heated on a laboratory Teflon~ pan equipped 28 with a surface thermometer to about 150C, and then the tiny pills are 1 3.~

1 added thereto to provide a homogeneous composition. Then, the compo-2 sition is molded into a cylindrical shaped and cooled to room tempera-3 ture. Next, the bioerodlble composition is placed into a wide mouth 4 capsule previously charged at its closed bot-tom first with a 30 9 stainless steel density member and then with an expandable drivlng 6 member. The driving member comprises 2 g of sodium chloride and 5 9 7 of sodium salt of polyacrylic acid available as Carbopol~ 934P
8 previously pressed into a tablet. The tablet is formed using an 9 18.2 mm tableting tool and 3 1/2 tons of compression force. The tablet compresses a final shape that corresponds to the internal shape 11 of the opening of the capsule, the expandable tablet has a surface in 12 contact w~th the pharmaceutical carrier tiny pill composition. Next, 13 the capsule is coated on its exterior surface up to its mouth by 14 dipping it into wall forming composition~ The wall forming composi-tion comprises 1.8 g of 91% cellulose acetate butyrate and 9% poly-16 ethylene glycol 400. The wall is applied from a 5~0 wt/wt solution of 17 methylene chloride methanol 90:10 v/v solvent system. The wall coated 18 dispenser is dried at about 25 to 30C for 24 hours. The dispenser 19 provided by this example delivers the tiny pills over time.

21 A dispenser is made according to the procedure set forth in 22 Example 1, except that in this example9 the benef1cial agent is 23 ivermec~in, and the pharmaceutically acceptable carrier comprises a 24 condensation copolymer of 3.9-bis(ethylidence)-2,4,8,10-tetraoxospiro[5,5] undecane and 1,6-hexanediol. The copolymer can be 26 prepared according to the synthesis described in United States Patent 27 No. 4 9 304,767.

~3~ ~7~

2 A dispenser is prepared by coating ivermectin in a fluld air 3 suspension machine with a composition of ethyl cellulose in ethanol to 4 surround the beneficial agent ivermectin with a wall of ethyl cellulose for protecting the tlny pills. After the solvent is vacuum stripped 6 form the tiny pills, the pllls are blended with the pharmaceutlcal 7 carrier of Example 1.

9 A dispenser system is prepared as follows: first, the body section of a capsule is positioned with its mouth in an upright position, 11 and a dense stainless steel element inserted into the hemispherical end 12 of the capsule. The dense element ~s machined and its shape made to 13 match the internal shape of the capsule. Next, a layer of an expand-14 able, swellable composition is charged on top of the dense element.
The composition comprlses 25X by weight of sodium chloride and 75% by 16 weight of polytethylene oxide) having a molecular weight of 200,000.
17 The expandable forming ingredients are blended in a commercial blender 18 with heat for 20 minutes to yield a homogeneous composition. The warm 19 composition is charged into the capsule formlng a layer that occupies about 1/3 of the capsule; next, a pharmaceut~cal carrier comprising 21 tiny pills of cellulose acetate surrounding a core of ivermectin is 22 charged into the open capsule. The cellulose acetate has an acetyl 23 content o~ 32% and the wall is formed from a methylene chloride 24 methanol solvent. The tiny pills are dispensed in a carrier comprising polylactide having a molecular weight o~ about 40,000 26 dissolved in methylene chloride. The blend is charged into the 27 capsule to form a homogeneous mass and vacuum dried at 60C. Then, 28 a solution of cellulose acetate, 15 wt ~, with an acetyl content of ~319~71 1 39.8X~ is prepared in a methylene chloride methano1 so1vent system and 2 the outside surface of the capsule coated with a semipermeable wall 3 while maintaining the mouth open. The wall is applied by dipping it 4 into the coating solution for 15 times, first for a 5 second dip, then for two ten second dips, then for a 30 second dip and then for 1 6 minute per dip wlth an intervening 5 minute drying period. Following 7 the dipping the deliver dlspenser is dried at room temperature, 72F, 8 about 22C, for 5 days. The procedure applies about a 2 mm thick g semipermeable wall.

11 A dispenser is provided comprising a tube-shaped 12 walled dispenser comprising an opened end and a closed end. The wall 13 comprises 50qo cellulose acetate butyrate, 45~ poly(sulfone) and 5~
14 acetyl tri-isopropyl citrate. The pharmaceutically acceptable carrier means comprises the polyhydroxyacetate ester polyglycolic acid 16 comprising tiny pills of a cellulose acetate wall surrounding the 17 beneficial agent impramine hydrochloride. The space consuming means 18 comprises poly(ethylene oxide) having a molecular weight of about 19 3~000,000 and 30% by weight of potassium chloride.

21 A dispenser is provided according to Example 5 wherein 22 the dispenser comprises a hydrophilic expandable member comprising a 23 70:30 ratio o~ sodium carboxymethylcellulose to sodium chloride, 24 1ubricated with 1% magnesium stearate compressed using 10,000 lbs of force in a Carver~ laboratory press.

27 An oral administrable delivery dispenser is provided 28 by coating a drug core o~ isosorbide dinitrate with a cellulose - ~3~9i~71 1 acetate wall having an acetyl content of 32X. A methylene chloride-2 methanol solvent is used as the vehicle for the cellulose acetate in 3 an air suspension coater. After the solvent is evaporated, the pills 4 are housed in a matrix composition made by wet granulation. The composition comprises 92.5% cellulose acetate, polyethylene oxide and 6 hydroxypropylmethylcellulose in equal amounts. Then, the granules are 7 blended in powdered hydroxypropylcellulose and hydroxy-propylmethyl-8 cellulose. The final stick matrix comprises 85~o tiny pills, 10%
g hydroxypropylcellulose, 3% hydroxypropylmethylcellulose, 1% cellulose acetate and 1 % polyethylene oxide. The wall of the dispenser com-11 prises cellulose acetate with an acetyl content of 32%, which wall in 12 one manufacture is deposited on the core by a spray-coating process.
13 In the above examples the drug can be present in the tiny pill in 14 various forms, such as unchanged molecules, molecular complexes, therapeutically acceptable salts such as hydrochlorides, hydrobro-16 mides, sulfates, oleates, and the like. For acid drugs, salts of 17 metals, amines9 or organic cations, quaternary ammonium salts can be 18 used. Derivatives of drugs such as esters, ethers and amides can be 19 used. Also, a drug that is water insoluble can be used in a form that is the water soluble derivative thereof to serve as a solute, and on 21 its release from the device is converted by enzymes, hydrolyzed by 22 body pH, or other metabolic processes to the original biologically 23 active form.
24 The amount of drug present in a tiny timed pill per se generally is about 10 ng to 50 mg, and the number of tiny pills in an oral 26 device ls about 5 to 1000, preferably 10 to 100. The tiny pills 27 comprising the wall and ~nner core of drug have a diameter of at least 28 1 mm to 7.5 mm, and in a presently preferred embodiment they have a 13~9~7~

1 diameter of 2 mm to 5 mm. For oral use, the delivery device compri- ;
2 sing the matrix and the tiny pills homogeneously or heterogeneously 3 housed therein can have a conventional shape such as round, oval and 4 the like.
An embodiment of the invention pertains to a method for deliver-6 ing a beneficial drug to an animal at a controlled rate, which method 7 comprises the steps of: (A) admitting into an animal a dispenser 8 comprising: (1) a wall that surrounds a lumen; (2) means in the lumen g for containing tiny timed pills, which means keeps its integrity while in the lumen; (3) a plurality o~ tiny timed pills in the means, which 11 tiny pills comprise a wall surrounding a drug; (4) means in the 12 lumen for occupying space for urging the means containing the tiny 13 timed pills from the lumen; and (5) a mouth in the wall communicating 14 with the means containing the tiny pills; (B) imbibing fluid through the wall into the lumen at a rate determined by the permeability of 16 the wall and ~he osmotic pressure gradient across the wall to cause 17 the means for occupying space to absorb fluid, expand and push the 18 means containing the tiny pills through the mouth; and thereby (C) 19 delivering the tiny timed pills comprising the beneficia1 agent to the 20 animal to produce a bene~icial effect over time.
21 It will be appreciated by those versed in the art, the present 22 invention makes available novel and useful delivery devices ~or 23 dispensing a beneficial drug over a prolonged period of time. Also, 24 it will be understood by those knowledgeable in the dispensing art 25 that many embodi~ents of this invention can be made without departing 26 from the spirit and scope of the invention, and the invention is not 27 to be construed as limited, as it embraces all equivalents therein.

Claims (7)

1. A dispenser for administering a beneficial agent, the dispenser comprising:
(a) a wall that surrounds an internal lumen, the wall comprising a composition that is permeable to Fluid and impermeable to a beneficial agent;
(b) means in the lumen for containing a plurality of tiny pills, said means maintaining its physical and chemical integrity while in the lumen;
(c) a plurality of tiny pills in the means, the tiny pills comprising:
(1) a beneficial agent; and, (2) a wall that surrounds the beneficial agent;
(d) means in the lumen for pushing the means comprising the tiny pills from the dispenser; and, (e) a mouth in the dispenser comprising a cross-section substantially equal to that of the lumen for delivering the tiny pills from the dispenser.

2. The dispenser according to claim 1, wherein the lumen comprises a density member exhibiting a specific gravity greater than one.

3. The dispenser according to claim 1, wherein the wall of the tiny pills is semipermeable.

4. The dispenser according to claim 1, wherein the wall of the tiny pill comprises an enteric composition.

5. The dispenser according to claim 1, wherein the wall of the tiny pill is erodible.

6. The dispenser according to claim 1, wherein the wall of the tiny pill is microporous.

7. The dispenser according to claim 1, wherein the wall of the tiny pill comprises a diffusional polymer.