WO1998002141A1

WO1998002141A1 - Interlocking osmotic device

Info

Publication number: WO1998002141A1
Application number: PCT/US1997/011525
Authority: WO
Inventors: Patrick S.-L. Wong; Felix Theeuwes; Liang C. Dong; Vincent J. Ferrari
Original assignee: Alza Corporation
Priority date: 1996-07-15
Filing date: 1997-07-01
Publication date: 1998-01-22
Also published as: AU3590497A

Abstract

The present invention is directed to a fluid-imbibing drug delivery device which is useful for the initial delayed delivery of an active agent formulation to a fluid environment of use, the initial delay period prior to startup or activation being of a predetermined length of time. The dispensing device is formed of a first and second housing that are in reversibly sliding telescoping interlocking arrangement with each other.

Description

INTERLOCKING OSMOTIC DEVICE

FIELD OF THE INVENTION

The present invention is related to the delayed delivery of an active agent. More particularly, it is related to interlocking osmotically-activated devices for dispensing active agents to a biological environment of use following an initial period of delay.

BACKGROUND OF THE INVENTION

Osmotic dispensing devices for delivery of therapeutically active agents are well known in the art. Such devices use an expansion agent to deliver an active agent formulation to an environment of use over a period of hours, days or months. The expansion agent absorbs liquid, expands, and acts to drive out the active agent formulation from the interior of the device in a controlled, constant or other preprogrammed manner. The osmotic expansion agent is used to controllably, usually relatively slowly, and over a period of time, deliver the agent. Osmotic devices have also been described for protonged and controlled delivery of one or more active agents where an initial delay of delivery is desired. US Patent No. 5,198,229, which is incorporated herein by reference, is directed to an osmotic device for delivery of an active agent to the upper gastrointestinal tract. The dispensing device comprises concentric housings that are in slidabiy telescoping arrangement with each other. A first expansion means imbibes fluid when placed in the stomach environment. This expansion means expands and pushes against a partition layer that in turn pushes against an active agent formulation. The active agent is delivered to the stomach environment through a small exit port in a controlled and continuous manner. After all the active agent has been delivered, the ι housings separate, the buoyancy chamber is exposed to the stomach

2 environment, thereby increasing the density of the device, and the device

3 sinks and exits out of the stomach

4 US Patent No 5,312,388, which is incorporated herein by reference,

5 describes the use of slidabiy telescopic concentric housings in an osmotic

6 device where delivery of more than one active agent is desired or where

7 separate dosings of one active agent are desired In a particular

8 embodiment, initial rapid delivery of a particular active agent is followed by

9 delayed delivery of the active agent A loading dose of the active agent is ιo dispensed as soon as the device enters the environment of use Prolonged ιι delivery is accomplished as a result of an expansion means that imbibes

12 fluid and expands to separate the concentric housings Upon separation,

13 the active agent contained within the housings is dispensed

14 US Patent No 5,312,390, which is incorporated herein by reference, is describes an osmotic device useful for the initially delayed delivery of an

16 active agent Slidabiy telescoping concentric housings separate following

17 absorption of fluid through the housing A fluid passage means is exposed

18 to the fluid environment and the active agent is expelled in a controlled and

19 continuous manner through an exit port at the end of the housing opposite

20 the fluid passage means

21 As can be observed in the above-referenced patents, osmotic devices

22 have been described that provide for an initial pulse of an active agent, that

23 provide for prolonged delivery of an active agent, and that provide for delivery

24 of more than one active agent However, there remains a continuing need for

25 improved methods and systems for delivering one or more active agents in a

26 reliable and reproducible manner ι SUMMARY OF THE INVENTION

2

3 We have observed that devices such as those described above will

₄ open in a predictable manner but that the agent contained in the device,

5 depending on its physical forms, is not always predictably released to the

6 environment of use at the desired location and concentration Therefore,

7 according to our invention, we have provided an osmotic device that will β deliver an active agent following a reproducible period of delay

9 Accordingly in one aspect, the invention is directed to a fluid-imbibing o delivery device comprising a first housing and a second semipermeable 1 housing that are in reversibly sliding telescoping interlocking arrangement 2 with each other The first housing contains an active agent formulation and 3 the second housing contains an expansion agent 4 In another aspect, the invention is directed to a fluid-imbibing device s for dispensing an active agent formulation following an initial preset delay 6 of startup of delivery The device comprises male and female housings 7 ireversibly sliding telescoping relationship with each other One of the s housings is semipermeable and the other contains an active agent 9 formulation The outer surface of the male housing and the inner surface 0 of the female housing are in interlocking arrangement with each other 1 2 DESCRIPTION OF THE DRAWINGS 3 The drawings are not drawn to scale, but are set forth to illustrate 5 various embodiments of the invention Like numbers refer to like structures 6 FIG 1 is a cross-sectional view of one embodiment of the delivery 7 device of the present invention, the device being in closed or prepared form 8 prior to placement in the fluid environment of use ι FIG. 2 shows the device of FIG. 1 in operation after placement in the

2 environment of use, showing the expansion chamber expanded and the first

3 and second housings of the device separated.

4 FIG. 3 is a side cross-sectional view of another embodiment of the

5 delivery device at the present in closed form.

6 FIG. 4 shows the device of FIG.3 in operation after placement in the

7 environment of use.

8

9 DETAILED DESCRIPTION OF THE INVENTION

10 ιι The present invention provides a device which is useful for the delivery

12 of one or more active agent formulations to a fluid environment of use

13 following an initial delay period prior to startup or activation of the device.

14 is Definitions

16 The phrase "initial delay period", as used herein, intends a

17 predetermined time period such as for greater than from about several

18 minutes to several hours and preferably for a period of from about 30 minutes

19 to about 10 hours after the initial delay period. The active agent is preferably

20 administered as a bolus, i.e., once the housings of the device have

21 separated, the dose of agent in the device is released in a short period of

22 time of 1 hour or less and usually within 45 minutes and preferably in less

23 than 30 minutes.

24 As used herein, the terms "therapeutically effective" amount or rate

25 refer to the amount or administration rate of the active agent needed to effect

26 the desired therapeutic, often beneficial, result.

27 With reference to the housings of the devices, "impermeable" is meant

28 that the material is impermeable to both fluids as well as other ingredients

29 contained in the dispensing device such that the migration of such materials

30 into or out of the device is so low as to have substantially no adverse impact ι on the function of the device during the delivery period By "semipermeable"

2 is meant that the material is permeable to fluid but impermeable to other

3 ingredients contained in the dispensing device and the environment of use

4 The term "active agent" as used herein refers to an agent, drug,

5 compound, composition of matter or mixture thereof which provides some

6 therapeutic, often beneficial, effect This includes pesticides, herbicides,

7 germicides, biocides, algicides, rodenticides, fungicides, insecticides, β antioxidants, plant growth promoters, plant growth inhibitors, preservatives,

9 antipreservatives, disinfectants, sterilization agents, catalysts, chemical ιo reactants, fermentation agents, foods, food supplements, nutrients, ιι cosmetics, drugs, vitamins, sex stenlants, fertility inhibitors, fertility promoters,

12 microorganism attenuators and other agents that benefit the environment of

13 use As used herein, the terms further include any physiologically or

14 pharmacologically active substance that produces a localized or systemic is effect or effects in animals, including warm blooded mammals, humans

16 and primates, avians, domestic household or farm animals such as cats,

17 dogs, sheep, goats, cattle, horses and pigs, laboratory animals such as is mice, rats and guinea pigs, fish, reptiles, zoo and wild animals, and the like

19 The active agent that can be delivered includes inorganic and organic

20 compounds, including, without limitation, drugs which act on the peripheral

21 nerves, adrenergic receptors, cholinergic receptors, the skeletal muscies

22 the cardiovascular system, smooth muscles, the blood circulatory system,

23 synoptic sites, neuroeffector junctional sites, endocrine and hormone

24 systems, the immunoiogical system, the reproductive system, the skeletal

25 system, autacoid systems, the alimentary and excretory systems, the

26 histamine system and the central nervous system Suitable agents may be

27 selected from for example, proteins, enzymes hormones, polynucleotides,

28 nucleoproteins, polysacchandes, glycoproteins, lipoproteins, polypeptides,

29 steroids, hypnotics and sedatives, psychic energizers, tranquilizers,

30 anticonvulsants, muscle relaxants, antiparkmson agents, analgesics, anti- ι inflammatoπes, local anesthetics, muscle contractants, antimicrobials,

2 antimalaπals, hormonal agents including contraceptives, sympathomimetics,

3 polypeptides and proteins capable of eliciting physiological effects, diuretics,

4 lipid regulating agents, antiandrogenic agents, antiparasitics, neoplasties,

5 antineoplastics, hypoglycemics, nutritional agents and supplements, growth

6 supplements, fats, ophthalmics, antiententis agents, electrolytes and

7 diagnostic agents a Examples of beneficial agents useful in this invention include

9 prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecaxylamine ιo hydrochloπde, procainamide hydrochlonde, amphetamine sulfate, ιι methamphetamine hydrochlonde, benzphetamine hydrochlonde,

12 isoproteronol sulfate, phenmetrazine hydrochlonde, bethanechol chloride,

13 methacho ne chloride, pilocarpine hydrochlonde, atropine sulfate,

14 scopolamtne bromide, isopropamide iodide, tπdihexethyl chloride, phenformin

15 hydrochlonde, methylphenidate hydrochlonde, theophyllme cholinate,

16 cephalexin hydrochlonde, diphenidol, meclizme hydrochlonde,

17 prochlorperazine maleate, phenoxybenzamme, thiethylperazine maleate, is anisindione, diphenadione, erythrityl tetranitrate, digoxin, isofiurophate,

19 acetazotamide, methazolamide, bendroflumethiazide, chlorpropamide,

20 tolazamide, chlormadinone acetate, phenaglycodol, allopuπnol, aluminum

21 aspirin, methotrexate, acetyl sulfisoxazole, hydrocortisone,

22 hydrocorticosterone acetate, cortisone acetate, dexamethasone and its

23 derivatives such as betamethasone, triamcinolone, methyltestosterone,

2 17-β-estradιol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,

25 17-β-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,

26 norethindrone, norethisterone, norethiederone, progesterone, norgesterone,

2 norethynodrel, indomethacin, naproxen, fenoprofen, sulindac, indoprofen,

28 nitroglycenn, isosorbide dinitrate, propranolol, timoloi, atenolol, alprenolol,

29 cimetidine, cionidine, imipramine, levodopa, chlorpromazine, methyldopa,

30 dihydroxyphenylalanme, theophyllme, calcium gluconate, ketoprofen, ι ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate,

2 vincamine, phenoxybenzamine, diltiazem, milrinone, captropril, mandol,

3 quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen,

4 tolmetin, alclofenac, mefenamic, flufenamic, difuninal, nimodipine,

5 nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil,

6 gallopamil, amlodipine, mioflazine, lisinopril, enalapril, captophl, ramipril,

7 enalaprilat, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, β chiordiazepoxide, diazepam, amitriptylin, and imipramine. Further examples

9 are proteins and peptides which include, but are not limited to, insulin, ιo colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary ιι hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone,

12 follicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing

13 hormone, bovine somatotropin, porcine somatropin, oxytocin, vasopressin,

14 prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH,

15 interferons, interleukins, growth hormones such as human growth hormone,

16 bovine growth hormone and porcine growth hormone, fertility inhibitors such

1 as the prostaglandins, fertility promoters, growth factors, and human is pancreas hormone releasing factor.

19 The term "active agent formulation" intends active agent optionally in

20 combination with pharmaceutically acceptable carriers and additional inert

21 ingredients. It is to be understood that more than one active agent may be

22 incorporated into the active agent formulation in a device of this invention,

23 and that the use of the term "agent" in no way excludes the use of two or

24 more such agents. The agents can be in various forms, such as uncharged

25 molecules, components of molecular complexes or nonirritating,

26 pharmacologically acceptable salts. Also, simple derivatives of the agents

27 (such as ethers, esters, amides, etc.) which are easily hydrolyzed by body

28 pH, enzymes, etc. can be employed. ι The dispensing devices of the invention find use, for example,

2 in humans or other animals. The environment of use is a fluid environment

3 and can comprise the stomach, the intestinal tract, or a body cavity such as

₄ the peritoneum or vagina. A single dispensing device or several dispensing

5 devices can be administered to a subject during a therapeutic program.

6 FIG. 1 depicts, in cross-sectional view, a first embodiment of the

7 delivery device according to the present invention. The device is shown in β closed or prepared form prior to placement in the environment of use.

9 Dispensing device 1 comprises a first housing 12 and a second housing 14. ιo First housing 12 and second housing 14 are in slidabiy telescoping ιι interlocking arrangement with each other. First housing 12 contains an active

12 agent formulation 22.

13 Second housing 14 contains an expansion agent 20 and an

14 impermeable partition 32. is First housing 12 and second housing 14 are shown to be ovoloid

16 in shape, but they may also be round, hexagonal or any other suitable

1 configuration. First housing 12 is shown to be a male housing and second is housing 14 is shown to be a female housing. First housing 12 and second

19 housing 14 at their ends have interlocking wall sections. The ridged, external

20 wall of first housing 12 and the ridged, internal wall of second housing 14

21 maintain the two housings together prior to and during activation of the

22 expansion agent 20 until a sufficient preestablished expanding driving force

23 is exerted on the housings. The end of first housing 12 is adapted to fit within

24 second housing 14. The edge 34 of the end of first housing 12 provides a

25 platform or ridge against which partition 32 abuts to receive the driving force

26 of expansion agent 20 to separate the two housings.

27 In operation, dispensing device 1 is placed in the fluid environment of

28 use and the expansion agent 20 begins to imbibe and absorb fluid through

29 second housing 14 from the environment. The expansion agent 20 expands,

30 exerting a driving force via partition 32 against ridge 34 of first housing 12 ι to begin to slidabiy separate first housing 12 from second housing 14. At a

2 predetermined time, first housing 12 and second housing 14 separate apart

3 from each other by the action of the expansion agent 20, via partition 32,

4 on edge 34 exposing the agent formulation 22 to the environment of use.

5 FIG. 2 shows the dispensing device 1 of FIG. 1 in operation. First

6 housing 12 has begun separating from second housing 14 by the expanding

7 driving force of expansion agent 20 on partition 32, which expansion agent 20

8 has expanded in size as a result of imbibing fluid from the environment.

9 FIG. 3 depicts, in side cross-sectional view, a second embodiment ιo of the delivery device according to the present invention. The device 50 ιι is similar to the device described above with regard to FIGS. 1 and 2,

12 but instead of a series of ridges, the interlocking arrangement comprises

13 a protuberance on each of the first housing 12 outer wall and the second

14 housing 14 inner wall. As shown in FIG. 4, the first housing protuberance is 52 interlocks with the second housing protuberance 54 until there is sufficient

16 force exerted by the expansion of the expansion agent 20 to cause

17 separation of the first housing 12 and the second housing 14 and delivery of

18 active agent formulation 22.

19 With reference to the embodiments shown in FIGS. 1-4, first housing

20 12 must be substantially impermeable in its entirety to the ingress of the

21 external fluid where necessary for substantially protecting the agent or

22 dosage form, or it may be semipermeable. Because first expansion agent 20

23 operates by imbibing external fluid, second housing 14 must allow fluid to

24 pass through for activating the expansion agent while being impermeable to

25 the ingredients of the expansion agent. Accordingly, the second housing 14

26 may be a microporous membrane or a screen, or may be of a composition

27 that is semipermeable, or a combination of these.

28 Housings 12 and 14 may optionally comprise additional ingredients

29 such as, for example, plasticizers. Impermeable and semipermeable

30 compositions suitable for use in housings 12 and 14, as well as suitable ι additives, are known in the art, examples of which are disclosed in US Patent

2 No. 4,874,388, which is incorporated herein by reference.

3 The housings are designed so they will not come apart until there is

4 sufficient driving force produced by expansion agent 20 to overcome the

5 interlocking force of the housing walls. The interlocking force is produced

6 when a portion of the outer diameter of the first housing is smaller than a

7 portion of the inner diameter of the second housing. When these portions

8 come together, further motion is prevented until the resistance of the walls to

9 deformation is overcome by the driving force of the expansion agent. ιo The delivery device of the present invention is nontoxic, biologically ιι inert, nonallergenic and nonir tating to body tissue, and it maintains its

12 physical and chemical integrity; that is, the device does not erode or degrade

13 in the environment of use during the dispensing period. It is within the scope

14 of the invention that the device be insoluble only during the period of intended is use and can thereafter dissolve away in the environment of use. Thus, a

16 dispenser is contemplated which is unaffected by its environment, solubility-

17 wise, at the situs of use or which, alternatively, is only slightly soluble during

18 the period of intended use, such that once its active agent content has been

19 removed it will dissolve or erode away.

20 The expansion agent or expandable driving agent 20 is nontoxic,

21 nonallergenic and biologically inert. In one embodiment, agent 20 comprises

22 an osmopolymer. Osmopolymers interact with water and aqueous biological

23 fluids and swell or expand to an equilibrium state. Osmopolymers exhibit the

2 ability to swell in fluid and to retain a significant portion of the imbibed and

25 absorbed fluid within the polymer structure. The expansion agent 20 in

26 another embodiment is an osmagent. Osmagents are also known as

27 osmotically effective solutes or compounds. Osmagents that can be used for

28 the purpose of this invention include inorganic and organic compounds that

29 exhibit an osmotic pressure gradient across a semipermeable, i.e., a fluid-

30 permeable wall. The expansion agent 20 in yet another embodiment is an ι osmagent dispersed within an osmopolymer. The expansion agent can be a

2 tablet or a layer, or a plurality of tablets or layers, and can be placed into

3 position in the device or it can be pressed into the device. The osmagent or osmopolymer can be in any suitable form such as particles, crystals, pellets,

5 granules, and the like, when pressed into a tablet layer or into the device.

6 Osmagents and osmopolymers are known in the art and are described in,

7 for example, US Patent Nos. 3,865,108, 4,002,173, 4,207,893, 4,327,725

8 and 4,612,008 which are incorporated herein by reference. In a further

9 embodiment, expansion agent 20 is an effervescent couple. Effervescent ιo couples are comprised of a dry compound or an anhydrous mixture of ιι compounds that, when intimately contacted by an external fluid, generate a

12 gas that exerts a pressure to drive the device. The couple often comprises a

13 solid acidic and a solid basic material that dissolve and react in the presence

14 of fluid imbibed into the device. Suitable materials are described in US Patent is No. 4,203,441 which is incorporated by reference herein.

16 Partition 32 is substantially impermeable to the passage of fluid, and

17 serves to restrict the passage of fluid present in the expansion agent into the is first housing. It operates to essentially maintain the integrity of the active

19 agent formulation 22 and the expansion agent 20. Additionally, partition 32

20 acts to insure that the expanding driving force generated by the expansion

21 agent 20 is applied directly against first housing 12 to effect the separation

22 of the first and second housings. Thus, partition 32 must be of sufficient

23 strength, thickness and rigidity to transfer the driving force against first

24 housing 12.

25 Representative impermeable materials useful as piston 32 are known

26 in the art and are described in, for example, US Patent No. 4,874,388 which

27 is incorporated herein by reference.

28 The active agent formulation comprises the active agent to be

29 delivered, as a liquid, solid, semisolid or thermo-sensitive composition,

30 generally in a carrier substance and with or without additional inert ι ingredients. The active agent formulation may additionally include dosage

2 forms containing the active agent which are capable of maintaining their

3 physical configuration and chemical integrity while housed within the

4 dispenser. These include, without limitation, tablets with or without a

5 density element; matrix tablets; spheres; pellets and elongated tablets;

6 capsules; elementary osmotic pumps, such as those described in

7 US Patent No. 3,845,770; mini-osmotic pumps, such as those described s in US Patent Nos. 3,995,631 , 4,034,756 and 4,111 ,202; and multichamber

9 osmotic systems referred to as push-pull and push-melt osmotic pumps, ιo such as those described in US Patent Nos. 4,320,759 and 4,449,983; ιι all of which patents are incorporated herein by reference.

12 The pharmaceutically acceptable carrier useful herein may include

13 more than one ingredient, such as, for example, buffers, viscosity regulating

14 vehicles, surfactants, dyes, permeation enhancers, proteinase inhibitors, is or other formulation ingredients and additives, as are known in the art.

16 The carrier may contain more than one active agent. The active agent

17 formulation can erode or disintegrate and can be in the form of a wax is formulation, a solid core or a tablet, for example. The formulation can

19 immediately dissolve upon exposure to fluid or it may erode slowly with

20 or without the presence of excipients for controlling erosion.

21 The active agent formulation can be designed in a multitude of ways

22 to provide a specific drug delivery profile. One embodiment may comprise

23 a formulation that contains a biologically acceptable solid surfactant which

24 is capable of slow dispersion in the environmental fluid. In another

25 embodiment, the formulation may contain a fluid-insoluble wax and a

26 surfactant so that the formulation is susceptible to erosion in the environment.

27 In still another embodiment, the formulation may be effervescent and provide

28 drug delivery in a finely dispersed form. This is accomplished by the addition

29 of a solid basic compound capable of evolving carbon dioxide in the presence

30 of an acid in the environment of use. Suitable basic compounds are ι disclosed in US Patent No. 4,265,874 which is incorporated herein by

2 reference. In a further embodiment, the formulation may include an osmotic

3 agent or solute, such as those described above with reference to the

4 expansion agent, so that when the formulation comes into contact with the

5 environmental fluid, it immediately dissolves. In yet another embodiment,

6 the agent formulation can be comprised of an agent and a thermoresponsive

7 composition. In this manner, the formulation would exhibit solid-like β properties at room temperature of 21°C and within a few degrees Celsius

9 thereof, and would have a melting point that approximates mammalian body ιo temperatures of 37°C and within a few degrees Celsius thereof. The term ιι "thermoresponsive" as used herein denotes the physical-chemical property

12 of an agent carrier composition to exhibit solid, or solid-like properties at

13 temperatures up to 31 °C and become fluid, semi-solid or viscous when

14 disturbed by heat at temperatures from 31 °C, usually in the range of 31 °C is to 45°C. Suitable materials useful as active agent carriers and excipients

16 are known in the art and are disclosed in US Patent Nos. 4,595,583 and

17 4,874,388, for example which are incorporated herein by reference.

18 The amount of active agent employed in the delivery device will be

19 that amount necessary to deliver a therapeutically effective amount of the

20 agent to achieve the desired result at the site of delivery. In practice,

21 this will vary widely depending upon the particular agent, the site of delivery,

22 the severity of the condition, and the desired therapeutic effect but will be

23 between about 0.01 ng and 1000 mg.

2 For proper delivery of the active agent, it may be desirable in some

25 instances for the dispensing device to deliver active agent to a particular

26 environment of use. Thus, it may be necessary for the device to remain in

27 a particular environment of use until such time as the agent formulation has

28 been delivered or, alternatively, for the device to pass through one particular

29 environment to another prior to delivering the agent formulation. In such

30 cases, additional elements are included in the device, or the device is ι designed in such a way to provide for such particular delivery. For example,

2 when the environment of use is the rumen of a ruminant animal, a density

3 element may be included in the dispensing device so that the device is

4 weighted to remain within the rumen during the dispensing period. Density

5 elements are known in the art and are discussed in, for example, US Patent

6 No. 4,874,388 which is incorporated herein by reference. When the

7 environment of use is the human stomach, it may be desirable for the device s to, for example, have a low initial density or to include air in that portion of the 9 internal compartment of the device that also contains the agent formulation. ιo In this manner, the device will float on the surface of the stomach contents ιι and remain in the stomach until the device opens to release the formulation.

12 Where it is desirable, on the other hand, to delay the release of an active

13 agent which, for example, is inactivated by the stomach contents or may

14 cause nausea or bleeding by irritating the gastric mucosa so that delivery in is the stomach is not desired, an enteric coating can be applied over at least

16 that portion of the housing of the dispensing device that is comprised of a

17 semipermeable membrane. Enteric coatings will remain intact in the stomach

18 but will rapidly dissolved once they arrive at the small intestine, thereafter

19 allowing fluid to be imbibed to activate the dispensing device. Enteric

20 coatings are well known in the art and are discussed at, for example,

21 "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA.

22 The total delay time prior to separation of the two housings of the

23 dispensing device and the total delivery time of the active agent formulation

24 can be controlled by a number of means to provide a sharp start-up of

25 delivery at a particular time with high accuracy. For example, the rate of fluid

26 imbibition into the expansion agent, and thus the rate of expansion of the

27 agent, can be controlled by the particular choice of semipermeable

28 membrane or microporous screen. The choice of such material with regard to

29 its rigidity will effect the accuracy of delivery time as well. The term "rigid" as

30 used for the purpose of this invention intends a material that imbibes less ι than about 30%, usually less than about 20% of fluid. The rate of expansion

2 of the expansion agent can also be controlled by the choice of composition of

3 the expansion agent as well as its viscosity. Compositions with a viscosity

4 greater than about 1 poise are preferred. The distance of overlap between

5 the telescoping portions of the first and second housings can influence the

6 period of time required for the two housings to separate. Combinations of

7 such control means may be used. Such control means are known in the art β and can be determined without undue experimentation.

9 The delivery device of the present invention can be manufactured ιo by standard manufacturing techniques. For example, in the preparation of ιι devices of the present invention, first housing 12 (the vessel) and second

12 housing 14 (the cap) are separately molded to the desired shape. Possible

13 semipermeable materials from which the second housing 14 may be prepared

14 include, for example, water flux enhanced Hytrel® polyester elastomers is (Du Pont), cellulose esters, water flux enhanced ethylene-vinyl acetate

16 copolymers, semipermeable membranes made by blending a rigid polymer

1 with water-soluble low molecular weight compounds, and other

18 semipermeable materials known in the art. Other materials and methods

19 for injection-molding the semipermeable membranes are further described

20 in U.S. Patent Application No. 08/330,892 which is incorporated by reference

21 herein. Impermeable materials from which the first housing 12 may be

22 prepared include, for example, polyethylene, polystyrene, ethylene-vinyl

23 acetate copolymers, Hytrel® polyester elastomers (Du Pont) and other

2 impermeable materials known in the art.

25 The device can be assembled as follows. Active agent formulation 22

26 is placed in first housing 12 at its end opposite the exit means, which end is

27 initially open; the formulation may be in the form of a liquid, solid, semi-solid, 2β powder or shaped tablet or tablets, for example. A "bilayer osmotic plug"

29 composed of impermeable partition 32 and expansion agent 20 is prepared in

30 a shape that will fit within second housing 14. The partition 32 and expansion ι agent 20 are compressed into a tablet on a rotary bilayer tablet press. The

2 bilayer osmotic plug is placed within the second housing 14 and the assembly

3 is forced over the end of the filled first housing 12 until partition 32 is adjacent

4 to the active agent formulation 22 to give a device as illustrated in FIG. 1.

5 The following examples are intended to illustrate but not to limit the

6 invention.

7 β EXAMPLE 1

9 ιo Delivery devices according to the present invention but without active ιι agent formulation are prepared as follows.

12 The first housing, with one closed end and one open end and ridges

13 on the external wall are prepared by injection molding pelletized ethylene

14 vinyl acetate copolymer (EVA, 9 wt% vinyl acetate). is The second housing is made by injection molding a composition

16 of 63 wt% polycaprolactone, 27 wt% polyethylene oxide and 10 wt%

17 polyethylene glycol to form a capsule with ridges on the internal wall.

18 An expanding layer is formed from the following dry components:

19 58.75 wt% sodium carboxymethyl cellulose (NaCMC), 30 wt% NaCI,

20 5.0 wt% hydroxypropylmethyl cellulose E-5 (Aqualon, Wilmington, DE),

21 and 1.0 wt% red ferric oxide. After mixing for 10 minutes, 5.0 wt% HPC-EF

22 (Aqualon, Wilmington, DE), dissolved in purified water is sprayed onto the

23 dry components to prepare granules. Magnesium stearate (0.25 wt%) is

24 added and the second expanding layer granules are thoroughly mixed for

25 5 min. An impermeable partition is formed by screening 5 wt%

26 hydroxypropylmethyl cellulose E-5 (Aqualon) and 95 wt% stearic acid

27 using a 40 mesh screen. The screened materials are added to a Hobart

2β mixer and blended for 10 min. Ethanol is added until a wet mass was formed.

29 The wet mass is screened through a 20 mesh screen and allowed to air

30 dry for 12 hours. The granules are then passed through a 20 mesh screen. 200 mg of the expanding layer granules and 50 mg of the partition layer granules are compressed together into a bilayer tablet in a rotary press. The tablet is placed into the injection molded second housing, expanding layer side down. The open end of the second housing is fitted over the open end of the first housing and the two housings are compressed together.

EXAMPLE 2

The opening time of the device of Example 1 is measured as follows. The device is placed in artificial intestinal fluid (USPXIX, intestinal fluid, simulated, TS; modified by not including enzymes). A plastic rod is glued onto the first housing of the device. The opening time is determined to be the time interval at which the second housing separates from the first housing. The opening time is about 6.5 hours after placement in the intestinal fluid. Modifications of the above-described modes for carrying out the invention that are obvious to persons of ordinary skill in the related arts are intended to be within the scope of the following claims.

Claims

ι WHAT IS CLAIMED IS:

2

3 1. A fluid-imbibing delivery device for dispensing an active agent

4 formulation to a fluid environment of use after an initial delay period, the

5 device comprising a first housing and a second housing, the first and second

6 housings being in reversibly sliding telescoping interlocking arrangement with

7 each other, the second housing being semipermeable and containing an β expansion agent and the first housing containing an active agent formulation. 9 2. The device of claim 1 wherein the first housing is impermeable. ιo 3. The device of claim 1 wherein the expansion agent is selected ιι from the group consisting of osmagents, osmopolymers, effervescent

12 couples, and mixtures thereof.

13 4. The device of claim 1 wherein the expansion agent has a

14 viscosity of greater than 1 poise.

15 5. The device of claim 1 , further comprising a partition disposed

16 between said expansion agent and said active agent formulation.

17 6. The delivery device of claim 1 , wherein the active agent

18 formulation is selected from the group consisting of liquid, solid, semi-solid,

19 effervescent, thermo-responsive formulations and mixtures thereof.

20 7. The device of claim 1 that further comprises an enteric coating.

21 8. The device of claim 1 wherein the second housing imbibes less

22 than 30% water.

23 9. In a fluid imbibing delivery device for dispensing an active agent

24 formulation to a fluid environment of use after an initial delay period, the

25 device comprising a male housing and a female housing in reversibly sliding

26 telescoping arrangement with each other, one of said housings being

2 semipermeable and the other of said housings containing an active agent

28 formulation; ι the improvement wherein the outer surface of the male housing and

2 the inner surface of the female housing are in interlocking arrangement with

3 each other.

4 10. The device of claim 9 wherein the interlocking arrangement

5 comprises a protuberance on each of the outer surface of the first housing

6 and the inner surface of the second housing. 11. The device of claim 9 wherein the interlocking arrangement

8 comprises ridges on each of the outer surface of the first housing and the

9 inner surface of the second housing. ιo 12. The device of claim 9 wherein each of the male and female ιι housings are prepared by injection-molding.