Patent US4235236 - Device for dispensing drug by combined diffusional and osmotic operations

United States Patent m

Theeuwes

[ii] 4,235,236 [45] Nov. 25, 1980

[54] DEVICE FOR DISPENSING DRUG BY

COMBINED DIFFUSIONAL AND OSMOTIC
OPERATIONS

[75] Inventor: Felix Theeuwes, Los Altos, Calif.

[73] Assignee: Alza Corporation, Palo Alto, Calif.

[21] Appl. No.: 11,121

[22] Filed: Feb. 12,1979

[51] Int.C1.3 A61M7/00

[52] U.S. CI 128/260

[58] Field of Search 128/222-223,

128/260, 271; 424/19, 22

[56] References Cited

U.S. PATENT DOCUMENTS

3,993,072 11/1976 Zaffaroni 128/260

4,060,084 11/1977 Chandrasekaran et al 128/260

4.111.201 9/1978 Theeuwes 128/260

4.111.202 9/1978 Theeuwes 128/260

4.111.203 9/1978 Theeuwes 128/260

4,127,127 11/1978 Wong et al 128/260

Attorney, Agent, or Firm—Paul L. Sabatine; Edward L. Mandell; Thomas E. Ciotti

[57] ABSTRACT

A device is disclosed for delivering an agent to an environment of use at a substantially constant rate over time. The device comprises a wall formed of a microporous material surrounding a compartment housing the agent and a thermodynamic member. The member comprises a film formed of an expandable, semipermeable material surrounding a means for expanding the member. The member can occupy any space-position in the compartment, and it also can be in contact with the wall. In operation, when the device is in the environment, agent is delivered from the device by diffusion through fluidfilled paths in the microporous wall, with external fluid simultaneously entering the compartment through the paths, also, fluid is imbibed by the member from fluid present in the compartment or directly across the wall causing it to expand, fill the compartment and continuously maintain agent in a substantially saturated state at the wall, thereby delivering agent at a substantially zero order rate of release from the device over a prolonged period of time.

Primary Examiner—C. Fred Rosenbaum

21 Claims, 5 Drawing Figures

1 2

tially constant rate by eliminating a receding boundary DEVICE FOR DISPENSING DRUG BY COMBINED interface and its accompanying dramatic drop in diffuDIFFUSIONAL AND OSMOTIC OPERATIONS sion delivery rate by providing a device that substantially maintains the agent at a saturated level at the FIELD OF THE INVENTION 5 boundary interface.

This invention pertains to a diffusional device. More Other objects, features, aspects and advantages of the particularly, the invention relates to a diffusional device invention will be more apparent to those versed in the for delivering an useful agent at a substantially zero art from the following detailed specification, taken in order rate of release over a prolonged and extended conjunction with the figures and the accompanying period of time. Specifically, the invention concerns a 10 claims, device that delivers a useful agent by a combination of

diffusional and osmotic physical-chemical principles for SUMMARY OF THE INVENTION

effecting controlled delivery over time. This invention concerns a device for delivering a

BACKGROUND OF THE INVENTION 15 beneficial a8ent to an environment of use. The device

consists essentially of a microporous wall surrounding a Devices designed for delivering useful agents are compartment containing agent and an expandable membecommg increasingly important articles of manufac- ber The member consists Qf an expandable semipermeture. The devices enjoy a wide application in commerce afele fi,m surrounding a means for expanding the memwhich includes the agriculture and pharmaceutical in- ber> which means fa ... from {he consisting

dustnes. Generally the devices operate by diffusion, 20 of an osmotically effective solute, a gas generating couand they consists of an active agent housed withm an , , „ ,, , T ..

,, . TC ° , ■ .. .. pie and a swellable polymer. In operation, agent is re

mert wall structure. If, the thermodynamic activity of , , - it_ , • ,_ ^ i5 J t_ • 1 u the agent is maintained substantially constant in the lefed from ^device by the combined physical-chemidevice, then a steady state will be established with the cal actions of the device and the member which actions release rate of agent from the device substantially con- 25 embrace agent diffusing through fluid-filled paths m the stant over time. This is commonly referred to as zero microporous wall and the member expanding to continorder release, a phrase suggested by physical-chemical uously flU the compartment, whereby the combined kinetics. actions causes the beneficial agent to be delivered from

If, however, the agent is present in the device in an the device at a controlled and substantially zero-order undersaturated amount, of if the agent is present in a 30 rate of release over a prolonged period of time, saturated amount with no excess agent phase, the ther- BRIEF DESCRIPTION OF THE DRAWINGS modynamic activity and concomitantly the release rate

will fall exponentially over time. This activity is com- In the drawings, which are not drawn to scale, but are monly referred to as first order release, a phrase also set forth to illustrate various embodiments of the invensuggested by physical-chemical kinetics. The zero order 35 tion, the figures are as follows:

release is the most preferred of the two different rates of FIG. 1 is a view of a device designed and manufacrelease for many applications, because in many applica- tured for orally administering a beneficial drug to a tions the amount of agent consumed as a function of warm-blooded animal;

time is constant, requiring a constant, zero order rate of FIG. 2 is an opened view of the device of FIG. 1, supply of agent in order to achieve and maintain a con- 40 which FIG. 2 illustrates the internal compartment and stant desired effect over time. It will be appreciated in tne thermodynamic member manufactured as an inteview of this presentation, that if a device is provided grally formed device;

that can exhibit a substantially zero order release over FIG 3 is a graph tnat iiiustrates the improved delivtime, the device would have a positive commercial use ery results obtained by the device of FIG. 1 and FIG. 2; and also represent a major contribution to delivery 45 FIG. 4 illustrates a device provided by the invention science. and designed for dispensing a drug in a body passage

OBJECT OF THE INVENTION wav sucn as the vagina or the ano-rectal passageways;

Accordingly, it is an immediate object of this inven- ^ g fe a side elevational view of an a atus with

tion to provide a device that has useful thermodynamic 50 .. , . - .„ „ „ ;„ j„„

^ .. J portions broken away to illustrate one procedure that

properties for delivering an agent over time. y , , - . .J „ , „, r.. , •

A tu v * r*u • • * 1 ■in can be used for forming the walls and film of the devices

Another object of the invention is to make available a ., , , , . b.

device that has an internal space consuming member for provided by the invention.

providing a device that exhibits a more constant, pre- r In the drawings and specification like parts in related

dictable release rate profile of useful agent. 55 flSures ^ identified by like numbers. The terms ap

Yet another object of the invention is to make avail- Peanng earller ln the specification and in the description

able a device having a constant activity source by pro- of the drawings, as well as embodiments thereof, are

viding a device having a wall and an internal expand- further detailed elsewhere m the disclosure,

able force that operates to maintain agent in the device DETAILED DESCRIPTION OF THE

in a concentrated state at the agent wall interface. 60 DRAWINGS

Still another object of the invention is to make available a device for delivering an agent whose release is Turning now to the drawings, in detail, which are controlled by Fickian diffusion through fluid-filled examples of various delivery devices of the invention, paths in a microporous wall with the agent activity at and which examples are not to be considered as limiting, the internal boundary layer kept at a substantially satu- 65 one example of a device is indicated in FIG. 1 by the rated level during the agent release period. numeral 10. In FIG. 1, device 10 comprises a body 11

Yet still another object of the invention is to make that can be shaped, sized, structured and adapted for

available a device that delivers an agent at a substan- easy placement and prolonged retention in an environ

ment of use for the controlled, continuous delivery of a beneficial agent thereto.

In FIG. 2, device 10 of FIG. 1 is seen in part openedsection, with its outer top layer partly sectioned-off, for elucidating the structure of device 10. In FIG. 2, device 5 10 comprises a body 11 having an exterior wall 12 that surrounds and forms a compartment 13. Compartment 13 contains an useful agent 14 and a thermodynamic member 15 that functions to maintain agent 14 in a substantially saturated state in compartment 13, espe- 10 cially during the time device 10 is in operation in a preselected environment of use. In FIG. 2, member 15 can, as in the embodiment shown, occupy a place near the center of compartment 13, or it can occupy any other place in compartment 13. Also, in an additional 15 embodiment member 15 can be partially or have a large part of its surface in contact with the inside surface of wall 12.

Wall 12 of device 10 is formed of a microporous material consisting of a plurality of microscopic-sized 20 interconnected pores or voids. The pores, illustrated as circles 16 for discussion herein, can be continuous with openings on both sides of wall 12, the pores can be interconnected through tortuous paths or regular and irregular shapes, including curved, curved-linear, ran- 25 domly oriented continuous paths, hindered connected paths and pores, and other paths and pores discernible by microscopic examination. Generally, materials possessing from 5 to 95% pores and having a pore size of from 50 angstroms to 100 microns can be used for male- 30 ing wall 12. The pores and connecting intra-wall paths can be preformed in wall 12 with microporous wall 12 then manufactured into device 10. In a presently preferred embodiment, wall 12 contains a multiplicity of pore-formers, not shown, that are dessolved or leached 35 from wall 12, which is integrally manufactured as device 10. In this embodiment, the pore-formers are removed when device 10 is in the environment of use thereby forming microporous wall 12 in the environment of use during operation of device 10. 40

The microporous paths of wall 12 are in one embodiment prefilled or they are filled in the environment of use with a diffusive medium permeable to the passage of agent 14. The medium is generally non-toxic and it does not adversely effect the device, the wall, the agent and 45 the environment. In one embodiment, the medium is a liquid phase comprised of a solution, a colloidal solution or a sol, the medium can be polar, semi-polar or nonpolar, or it can be a liquid present in the environment of use, including water, biological fluids, saline and buff- 50 ers.

Thermodynamic member 15 in compartment 13 of device 10 consists essentially of a film 17 made of a semipermeable polymer that is essentially impermeable to the passage of solute, gas and compounds, and per- 55 meable to the passage of fluid present in compartment 13. Film 17 is flexible and elastic, or it contains a plasticizer that imparts flexibility and expandability to member 15. Film 17 surrounds a means 18 for expanding member 15, and it, does not contain any beneficial or 60 useful agent, including drug. Member 15 can occupy any position in compartment 13, or member 15 can occupy a position in compartment 13 in contact with wall 12. In this latter position, semipermeable film 17 of member 15 is in contact with microporous wall 12, 65 defining and forming thereby, the functional equivalent of a semipermeable microporous laminate. In' one embodiment, means 18 is an osmotically effective solute

that exhibits an osmotic pressure gradient across film 18 against fluid in compartment 13. In operation, solute means imbibes fluid into member 15 from fluid in compartment 13 or across the laminate thereby enlarging and expanding member 15 to continuously fill compartment 13. In another embodiment, means 18 is a gas generating couple. In operation, couple means 18 imbibes fluid into member 15, in the manner described, wetting the couple and causing it to react and generate gas that enlarges and expands member 18 unidirectional or multidirectional in compartment 13. In another embodiment, means 18 is a lightly cross-linked polymer. In operation, polymer means 18 absorbs fluid that enters member 15, or across the laminate, causing it to swell and expand member 15. In all of these embodiments, as member 15 expands and fills space in compartment 13 it correspondingly continuously reduces or decreases the amount of space available for agent 14. This continual decrease in space substantially maintains agent 14 in a substantially saturated phase as there is less space and fluid available to the agent. The formation and maintenance of the saturated phase presents agent 14 to wall 12 at substantially the same rate and amount throughout the release period, thereby effecting for device 10 a zero order release rate.

FIG. 3 illustrates the results obtained with devices made according to this invention. In FIG. 3, A-C represents the release rate profile for a device made without a means for presenting a constant, saturated amount of agent to a release rate controlling wall. For this condition, a steady-state exist from A to B with a rapid drop from B to C as the agent wall interface is depleeted of saturated agent. Also, in FIG. 3, D-F represents the release rate profile for a device made according to this invention having a means that concentrates that agent for presenting a constant, saturated amount of agent to the release rate controlling microporous wall. For this condition, a steady-state exists for the increased prolonged period of time from D to E with a decline from E to F as substantially all of the agent is released by the device. This latter device exhibits zero order release rate kinetics.

FIG. 4 shows a device 10 designed, sized and styled for easy placement and comfortable retention in a body passageway, such as the vagina or the ano-rectal passageway. Device 10 has an elongated, cylindrical, selfsustaining shape with a pointed lead-end 20, a base-end 21, and it is equipped with a manually controlled cord 22 for easily removing device 10 from a body passage. Device 10 of FIG. 4 is structurally identical with device 10 of FIGS. 1, 2 and 3, as described above, and it operates in a like manner with member 15 expanding to 15a for continually occupying area in compartment 13. In an optional embodiment, not shown, member 15 can be in contact with wall 12, as described in FIG. 3. Device 10 of FIG. 4 in one embodiment contains a drug designed for release and absorption by the vaginal, or the rectal mucosa.

FIG. 5 illustrates an air-suspension apparatus 30 that can be used for carrying out the wall forming steps of the invention. In FIG. 5, apparatus 30 is composed of a cylindrical, columnar chamber 31 having an upper end 32 that can be opened for receiving materials. Chamber 31 has a conical section 33 at its lower end and that is equipped with a screen 34 for preventing materials from falling out of chamber 31.

Chamber 31 is joined to an enlarged elbow 35 that serves as an air duct attached to heater 36 and blower 37

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Device for dispensing drug by combined diffusional and osmotic operations