WO1994007562A1

WO1994007562A1 - Highly controllable pulsatile delivery device

Info

Publication number: WO1994007562A1
Application number: PCT/US1993/009180
Authority: WO
Inventors: James M. Davenport; James B. Eckenhoff; Sally A. Tao; Jeremy C. Wright; Terry L. Burkoth
Original assignee: Alza Corporation
Priority date: 1992-09-29
Filing date: 1993-09-27
Publication date: 1994-04-14
Also published as: ZA937146B; MX9305965A; AU5292793A; TW245642B

Abstract

Delivery capsules which include a beneficial agent and an activating mechanism (15) in separate compartments separated by a movable partition (14) are designed to deliver the beneficial agent in a pulsatile manner through an orifice (13). The pulsatile delivery is achieved by a pair of guide members (21, 23) inside the capsule (11), one secured to the capsule itself and the other to the movable partition. The guide members, which may be a shaft (21) and sleeve (23), a shaft (128) and ring (129), or some similar combination of elements, guide the motion of the partition along the axis (12) of the capsule. The motion may be linear or rotational in a screw-type manner, depending on whether or not the shaft is threaded. A series of stops or detents (22) is formed on one of the guide members and one or more catches or detent-engaging members (27) is formed on the other. The catches (27) check the movement of the partition and permit such movement to occur in pulses as the pressure rises above a threshold level. The number and spacing of detents (22) establish the number and frequency of the pulses, and the pulsing function operates independently of the sealing contact between the partition and the inner wall of the capsule.

Description

HIGHLY CONTROLLABLE PULSATILE DELIVERY DEVICE

FIELD OF THE INVENTION This invention lies in the field of controlled- or sustained- release systems for the delivery of drugs, nutrients and the like. In particular, this invention relates to delivery systems which are generally in the form of capsules designed to release a beneficial agent through an orifice in the capsule, the release occurring in a pulsatile manner as the result of internal pressure.

BACKGROUND OF THE INVENTION Osmotic delivery capsules, commonly referred to as "osmotic pumps," function by virtue of walls which selectively pass water into the capsule reservoir. Absorption of water by the capsule through these walls is driven by a water-attracting agent in the capsule interior which creates osmotic pressure across the capsule wall. The water-attracting agent may be the beneficial agent itself whose controlled release is sought, but in most cases it is a separate agent specifically selected for its ability to draw water, this separate agent being isolated from the beneficial agent at one end of the capsule. In either case, the structure of the capsule wall does not permit the capsule to expand, and as a result, the water uptake causes discharge of the beneficial agent through an orifice in the capsule at the same rate that water enters by osmosis.

The terms "osmotically effective" and "osmotically active" are used in the literature to characterize the fluid-attracting agent which drives the osmotic flow. Certain agents of this type are termed "osmagents," which denotes water-soluble compounds to which the capsule wall is not permeable. Further osmotically effective agents are water-swellable polymers, and when used in this manner such polymers are termed "osmopolymers." Osmagents and osmopoly ers may be used individually in a capsule or they may be combined. In cases where the osmotically active agent is separated from the beneficial agent by a movable partition or piston, the osmotically active agent and the semipermeable compartment in which it resides may be referred to as an "osmotic engine."

SUBSTITUTESHEET Many protocols or situations require, or would benefit from, an intermittent or pulsatile release of the beneficial agent from the capsule. This is true for the administration of a variety of drugs, medicaments and nutriments, in a range of environments extending from veterinary medicine to human drug administration, as well as hobby situations such as fish tanks. The reasons vary, and may address such needs as mimicking a natural intermittent physiological release, allowing for periods of restoration of certain bodily functions between administrations, or adhering to preestablished feeding or dosing protocols. In addition, a pulsed release may increase the therapeutic index of some drugs which would permit a lower total dose without loss of efficacy. Other examples abound.

Included in the patent literature relating to pulsatile osmotic pumps is U.S. Patent No. 4,777,049, issued October 11, 1988 to Magruder, P.R., et al . The pulsatile effect in this patent is achieved by the inclusion of a modulating agent with the beneficial agent to be delivered. The modulating agent is selected on the basis of its solubility in the delivery medium relative to the beneficial agent, and the pulsatile effect results from one of the two falling below its saturation point, causing more of the other to go into solution and thereby be released. The number of pulses one may obtain in this manner is limited, however, and it is difficult to achieve periodic pulses. The system of U.S. Patent No. 4,723,958, issued February 9, 1989 to Pope, D.G., et al . achieves the pulsatile effect by alternating layers of beneficial agent with layers of inert material. As it is being released, however, the beneficial agent emerges at a slow rate. The system of U.S. Patent No. 4,842,867, issued June 27, 1989 to Ayer, A.D., et al., is also a layered system, and is best intended for a low number of pulses. Layered systems are also disclosed by Wong, P.S.L., et al., U.S. Patent No. 4,874,388, issued October 17, 1989; Wong, P.S.L., et al . , U.S. Patent No. 4,957,494, issued September 18, 1990; and Wong, P.S.L., et al., U.S. Patent No. 5,023,088, issued June 11, 1991. The system of U.S. Patent No. 5,209,746, issued May 11, 1993 to Balaban et al . achieves a pulsatile effect by the presence of either protrusions or indentations along the interior wall surface of the device which act as resistance means to prevent movement of the sealing partition within the device. The partition thus acts as the detent-engaging element, being released from its contact with the protrusion or indentation and moving forward to the next protrusion or indentation once a threshold pressure across the partition, developed within the device as a result of the osmotic action of the osmotic pump, is exceeded. Therefore, the pulsatile function and the sealing function are the same, embodied in the partition, and are dependent on each other. This greatly limits the ranges of control and variability that can be achieved. Devices of the types disclosed in the above patents are limited both by their physical configurations and their reliance on the chemicals retained inside them for the pulsatile effect. Control over the intensity and spacing of the pulses which these devices can produce is limited, as is the number of pulses which can be delivered by a single device of dimensions practical for its use. Reliability and predictability are also problems in certain cases.

These and other limitations and disadvantages of known pulsatile delivery systems are addressed by the present invention.

SUMMARY OF THE INVENTION The present invention is directed to delivery devices which include a beneficial agent and an activating mechanism in separate compartments separated by a movable partition, which devices are designed to deliver the beneficial agent in a pulsatile manner through an orifice. The pulsatile delivery is achieved by a pair of guide members inside the capsule, one affixed to the capsule itself and therefore stationary, and the other affixed to the partition and therefore movable, with a series of stops or detents along either the stationary member or the movable member and one or more catches or detent-engaging members on the other, to check the movement of the partition and permit such movement to occur in pulses as the pressure rises above a threshold level. The number and spacing of detents establish the number and frequency of the pulses, and the pulsing function operates independently of the sealing contact between the partition and the inner wall of the capsule. Thus, the present invention resides in a delivery capsule which produces an intermittent or pulsatile release of beneficial agent by virtue of the structure of the capsule itself rather than the chemical composition of materials contained in the capsule or their arrangement in the capsule. The capsule includes a movable partition which divides the capsule interior into two compartments, a first compartment to contain a beneficial agent and a second compartment to retain an activating mechanism, such as an osmotically active agent. The two compartments vary in volume, with the second compartment expanding or increasing and the first compartment decreasing in volume, as the partition travels longitudinally within the capsule in response to pressure provided by the activating mechanism, such as, in the case of an osmotically active agent, the fluid flow into and the resulting expansion of the osmotically active agent. The guide members referred to above may take the form of a shaft and sleeve, a shaft and ring, a cylinder and plug, or any other such combination permitting one member to travel longitudinally within the capsule relative to the other while maintaining a seal around the partition to separate the two compartments of the capsule. The travel may be linear or in a helical or screw-type manner, depending on whether or not the contact between the two guide members is threaded. A series of detents are formed on one of the two guide members, these detents engaged by a detent-engaging element or series of such elements on the other guide member. The detent-engaging element engages the detents in succession as the movable guide member travels along the stationary guide member. Each detent offers resistance to the travel of the movable guide member, thereby holding the partition stationary relative to the capsule, as pressure increases in the activating mechanism compartment. When the pressure differential between the two compartments reaches a level great enough to overcome the resistance offered by the detent, the detent escapes its engagement with the detent-engaging element and the partition moves in response to the pressure differential. The movement of the partition continues until the detent-engaging element once again engages a detent, which once again immobilizes the partition within the capsule while the pressure again increases in the activating compartment. For a fixed diameter capsule, the volume of beneficial agent delivered by the pulse is determined by the distance between successive detents, and the number of pulses which a single capsule can-deliver is determined by the total number of detents.

In certain embodiments of the invention, the movable and stationary members have a screw-type relation, and the movable member rotates relative to the stationary member in a helical rotation path. The movable member may for example be a screw with detents periodically spaced along the thread path, and the stationary member a thread follower with catches to engage the detents. Alternatively, the movable member may be an internally threaded cylinder, again with detents along the thread path, and the stationary member a shaft extending from one end to the device end wall into the cylinder interior with catches to engage the threads and detents. As further alternates, the stationary member may be the threaded member, either internally or externally threaded, with the moving member containing the thread follower and catches. There may be one detent per screw revolution, or there may be multiple detents per revolution.

Regardless of which configuration is used, the screw-type relation offers a number of advantages. For example, the rate of travel of the partition along the capsule axis, and hence the rate of release of the beneficial agent from the capsule, can be regulated by appropriate selection of the pitch of the screw threads. In addition, the screw-type relation allows one to minimize the length of the capsule, and to maximize the number of pulses per unit length of the capsule. One example of a pair of guide members in accordance with the invention is a shaft and sleeve combination. In the initial condition of the capsule, the shaft resides inside the sleeve and the partition is positioned relative to the capsule shell so that the volume of the beneficial agent compartment is at a maximum. In embodiments of the invention in which the shaft is affixed to the movable partition and the sleeve is affixed to the capsule shell, activation of the activating mechanism, such as the gradual imbibition of moisture by the capsule into an osmotically active agent on the osmotic engine side of the partition, exerts pressure on the partition which causes the shaft to be drawn out of the sleeve in steps, each detent holding back the partition until a sufficient buildup of pressure is achieved. In embodiments in which the shaft is affixed to the capsule shell and the sleeve is affixed to the partition, the moisture imbibition or other activation causes an analogous effect, except that the sleeve is drawn over the shaft. In both cases, the moisture imbibition (or other activating mechanism) causes the sleeve and shaft to be drawn apart.

In preferred embodiments of the invention, the capsule shell is cylindrical with a smooth-walled interior, and the fit of the partition is close enough to prevent the passage of fluids around it. Thus, as the partition travels longitudinally within the capsule, the partition maintains sealing contact with the capsule wall continuously during the travel of the partition. This provides the advantage of maintaining the activating mechanism, such as an osmotically active agent, a fluid or a gas-generating composition, for example, separate from the beneficial agent both when the partition is stationary and when it is in motion. Furthermore, the placement of the detents and the detent-engaging element on the shaft and sleeve rather than on the capsule wall affords a wide range of control of the frequency of the pulses, since the frequency can be controlled by varying the dimensions of the shaft and sleeve, by varying the manner in which the sleeve engages the detents, and by selecting the materials of construction and the sizes and shapes of the engaging elements to control the resistance which the detent- engaging element offers to its disengagement from the detents. Thus, by isolating the pulsing function from the sealing function of the partition, wider ranges of control and variability are achieved.

Further preferred embodiments and their features, and further objects and advantages of the invention, will be apparent from the description which follows.

BRIEF DESCRIPTION OF THE DRAWINGS FIGS, la, lb and lc are cross section views of one example of a delivery device in accordance with the present invention. FIGS, la and lb are longitudinal cross sections of the device with the partition at two extreme ends, respectively, of its path of travel within the device. FIG. lc is an enlarged cross section of the shaft and sleeve portions of the device. FIGS. 2a, 2b and 2c are cross section views of a second example of a delivery device in accordance with the present invention. FIGS. 2a and 2b are longitudinal cross sections of the device with the partition at two extreme ends, respectively, of its path of travel. FIG. 2c is a transverse cross section taken along the line 2C-2C of FIG. 2a.

FIG. 3 is a cross section view of a further example of a delivery device in accordance with the present invention.

FIG. 4 is a cross section view of yet another example of a delivery device in accordance with the present invention, this device being a ru inal bolus.

FIGS. 5a through 5e are views of a further example of a delivery device in accordance with the present invention, which incorporates a screw-type motion of one of the guide members relative to the other rather than a strictly linear motion. FIG. 5a is a longitudinal cross section view of the device. FIG. 5b is a side view of the threaded shaft of the device, and FIG. 5c is a transverse cross section view of the threaded shaft taken along the line 5C-5C of FIG. 5b. FIG. 5d is a side view of the partition and the thread follower of the device, and FIG. 5e is a top view of the partition and resiliently mounted detent catches.

FIG. 6 is a cross section view of a sixth example of a delivery device in accordance with the present invention.

FIG. 7 is a cross section view of a seventh example of a delivery device in accordance with the present invention.

FIG. 8 is a plot of the cumulative amount of formulation released from a mechanically activated device in accordance with the invention vs. time, illustrating the pulsatile delivery behavior of the device. FIGS. 9a and 9b are plots of two tests showing the cumulative amount of formulation released from an osmotically activated device in accordance with the invention vs. time, illustrating the pulsatile delivery behavior of the device.

FIG. 10 is a plot of the cumulative amount of drug released from an osmotically activated device in accordance with the invention vs. time, illustrating the pulsatile delivery behavior of the device. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In preferred embodiments of the invention, the capsule is an elongated body of revolution, such as a circular cylinder, and the guide members are a shaft and shaft-engaging member, each of circular cross section as well. It is further preferred that the capsule shell, shaft and shaft-engaging member are coaxial along the longitudinal axis of the capsule.

The detents may be of any configuration, either symmetrically or asymmetrically arranged relative to the axis of the capsule, and either continuous around the axis of the capsule or discontinuous. In embodiments where the members are not screw-threaded and the travel of the movable guide member is linear along the axis of the capsule, preferred detents are those which are circular in shape, extending around the full outer circumference of the shaft or the inner circumference of a sleeve-shaped shaft-engaging member.

Likewise, the detent-engaging member may be of any configuration depending on the configuration of the detents, and the detent-engaging member may engage only one of the detents or two or more at the same time.

In embodiments involving a shaft and sleeve combination, the detents are a series of protrusions or stops on the shaft surface, and the detent-engaging element consists of a projection, continuous or discontinuous, on the inner surface of the sleeve and extending inwardly toward the shaft, the projection engaging a single detent. The resiliency of the engagement is preferably provided by the detent-engaging member. This may be achieved in a variety of ways, including the use of elastic materials for the construction of the sleeve and the inclusion of longitudinal slots in the sleeve to allow a resilient expansion. The projection is preferably located at the end of the sleeve through which the shaft passes, and for the circular detents referred to above, the preferred projection is an inwardly directed flange extending around the inner circumference of the sleeve and is continuous except where it is interrupted by one or more longitudinal slots in the sleeve. In further preferred embodiments, the flange is divided into segments by two or more such slots, in other words, the sleeve terminates in two or more prongs with inwardly directed teeth to engage the detents. Relaxation of the engagement between the teeth and any single detent results from the spreading of the prongs by the detent which occurs when the pressure differential exceeds the threshold required to force the detent past the prong teeth. Three- and four-prong arrangements are preferred.

The resistance offered by the prongs may vary widely, in accordance with the dimensions of the capsule and its internal parts and the needs of the pulsatile release effect which is sought to be achieved. The resistance may be expressed in terms of the threshold pressure differential which is sufficient to force a detent past the prongs. In terms of threshold pressure differential, the most typical values will be at least about 0.01 psi to about 100 psi, preferably between about 0.5 psi and about 15 psi, acting upon the partition. The system of the invention is designed with the proper spring constant to obtain the desired threshold pressure differential .

The time intervals between pulses may be as short as two or three minutes, although the most typical values will be from about 2 hours to about 120 days, and preferably from about 6 hours to about 20 days.

The number of detents is not critical to the invention, and may vary widely in accordance with the type of beneficial agent, the purpose of its administration, and the needs of the environment in which the capsule is to be placed. In most applications, the number of detents will be at least three, and preferably at least five. The detents are preferably positioned at substantially equal intervals along the length of the shaft, although the intervals may be unequal, depending on the dose profile or regimen desired. Their spacing is not critical to the invention, and may vary widely as well. The spacing, together with the dimensions and configurations of the other elements of the capsule, will determine the frequency of the pulses. The activating mechanism which is utilized in the present invention to activate the detent-engaging mechanism may be selected from any mechanism which provides a delivery of flow at sufficient pressure to ultimately disengage the detent. Such mechanism may be a dynamic system or a static system. Dynamic systems include, but are not limited to, osmotic engines; thermal systems; mechanical systems such as pumps using, for example, rotating mechanisms, pistons or vanes (the Harvard^® syringe pump and intravenous pumps being examples) or osmotic action (the Alzet^® osmotic pump being an example); flow resulting from vapor pressure of fluid; and flow resulting from chemical or electrochemical reactions such as those that generate gaseous products (for example, the electrolysis of water). Static systems include, but are not limited to, elastomeric systems such as those using an inflated bladder or other form of compressed gas; spring-loaded chambers or pistons; and systems dependent on gravity, such as displacement in height (an intravenous bottle being one example).

To achieve crisp pulses, i. e. , a sharply step-wise curve of delivery volume vs. time with clearly delineated rise times and decay times, preferred embodiments of the invention include a capacitance means in the activating mechanism compartment which provides an element of capacitance to the detent-engaging element. The term "capacitance" in this context is used to denote the gradual absorption and storage of the pumping energy (in the form of pressure) until the threshold is reached and the capacity for storage of the detent mechanism is exceeded, at which time the stored energy is spontaneously released. The capacitance means may be a pocket of compressible fluid such as, for example, a volume of water, or a bubble or pillow of gas such as air or an inert gas. Alternatively, the capacitance means may be a structure such as a spring; a compressible material such as polymeric or other foam; a diaphragm; a bellows; and the like; or combinations of these.

While this invention is of broad scope and capable of application to many different types of delivery capsules and agents to be delivered by such capsules, the basic elements of the invention and their functions are most easily understood by examination of certain specific embodiments.

Turning now to the Figures, which are not drawn to scale but are presented for purposes of illustration, FIGS, la, lb and lc depict, in cross section, one example of a capsule in accordance with this invention. The capsule 11 is a cylindrical body with a circular cross section and a longitudinal axis 12, an exit orifice 13 at one end, and a partition 14, also of circular cross section, dividing the capsule interior into a beneficial agent compartment 15 for containing a beneficial agent and a compartment 16 (or "osmotic engine") for containing an osmotically active agent. The partition 14 is a single-piece piston which moves in the direction indicated by the arrow 17 upon expansion of the osmotically active agent. While the entire shell 18 of the capsule is formed of a moisture-permeable (semipermeable) material, the osmotically active agent and the beneficial agent formulation are selected such that only the osmotic engine 16 undergoes any substantial expansion due to moisture absorption. FIG. la shows the starting position of the partition 14 providing the beneficial agent reservoir 15 with its maximum volumetric capacity, and FIG. lb shows the final position of the partition 14 with the osmotic engine 16 having fully expanded due to moisture absorption and substantially all of the beneficial agent having been forced out of the capsule through the exit orifice 13.

Extending backward from the rear surface of the partition 14 is a shaft 21 with a series of detents 22, all generally frusto-conical in shape, on its outer surface. Secured to the inner wall of the capsule shell 18 is a sleeve 23 with an opening 24 at its forward end to receive the shaft 21. The shaft 21 and sleeve 23 are each of circular cross section and each is coaxial with the capsule 11. The forward end of the sleeve contains a series of slots 25 which are parallel to the longitudinal axis 12 of the capsule, open-ended at the forward end 26 of the sleeve, thereby dividing the forward end of the sleeve into semi-rigid but resilient prongs. Extending inward toward the shaft from the forward end of the sleeve 23 are a series of four arc-shaped projections 27, one at the end of each of the four prongs formed by the slots 25.

As shown in the enlargement of FIG. lc which shows a projection 27 at the end of the sleeve raised slightly above the detents 22 on the shaft for purposes of illustration, each projection has two angled surfaces 30,31 which mate with correspondingly angled surfaces 32,33 on each detent. When the projection 27 and a detent 22 are engaged, the corresponding surfaces of the same angle are in contact. When the threshold pressure differential is achieved and the force on the shaft in the direction of the arrow 17 is sufficient to urge the detent past the projection, the protruding tip 34 of the projection between the two angled surfaces 30,31 passes the protruding edge 35 on the detents to contact the adjacent angled surface 37. The resilient force of the prong urges the projection 27 inward until it comes to rest between the next two angled surfaces 36,37. In this manner, the resilient force of the prong itself adds to the forces pushing the beneficial agent out of the capsule. FIGS. 2a, 2b and 2c depict cross sections of a second example of a capsule 41 in accordance with this invention. One difference between this capsule and the capsule of FIGS, la, lb and lc is that the sleeve 42 is affixed to the partition 43 rather than the capsule shell, and the shaft 44 is affixed to the capsule shell. Accordingly, the shaft 44 remains stationary while the sleeve 42 moves with the partition. A second difference is that the sleeve 42 contains three longitudinal slots 45 (FIG. 2c), and hence three prongs, rather than four. With slight modifications to the angles of the contacting surfaces, the sleeve 42 and shaft 44 are otherwise identical to those of FIGS, la, lb and lc, and operate in the identical manner.

A further difference in FIGS. 2a, 2b and 2c is that the partition 43 has two parts 46, 47, joined by springs 48. The space 51 surrounding the springs is occupied by air which compresses as the springs compress. Only the forward part 46 is rigidly secured to the sleeve 42. This construction permits the rear part 47 of the partition to move forward independently in response to the expansion of the osmotic engine, compressing the springs 48 and the bubble of air 51 surrounding the springs, and thereby transferring some of the energy of the osmotic engine to the springs and the air bubble, which collectively act as a capacitance means. By the time the threshold pressure is exceeded, the springs will be compressed and the air bubble pressurized, and when the projections on the prongs release the detents 49, the springs and pressurized air bubble help force the forward part 46 of the partition forward, thereby adding to the force pushing the beneficial agent out the orifice 50. A still further difference is that the shell of the capsule 41 is constructed in two parts, a forward part 54 initially surrounding the beneficial agent reservoir 56 and constructed of a material which is not permeable to moisture, and a rear part 55 which initially surrounds the osmotic engine compartment 57 and is moisture- permeable. This assures that moisture imbibition will occur only in the osmotic engine and will not dilute the beneficial agent prior to its release from the capsule.

FIG. 3 depicts in cross section a further embodiment of the delivery device of the present invention, capsule 61. The shell of capsule 61 is constructed in two parts, a forward part 62 initially surrounding the beneficial agent reservoir 64 and made of an impermeable material and including an exit orifice 65, and a rear part 66 initially surrounding the osmotic engine compartment 68 and made of a semipermeable material. Impermeable section 62 has an inwardly notched edge 63 around the circumference of its open end for inserting in mating arrangement into the open end of semipermeable section 66.

Sleeve 70 of capsule 61 is shaped in a circular U-shape with a notch 72 on the outer circumference of the upper portion of its outer wall. Sleeve 70 is affixed to the open end of impermeable section 62 of the capsule shell at notch 72. There are four prongs 74 formed from four longitudinal slots in the inner wall of sleeve 70, each prong having an arc-shaped projection 75 at its end. Partition 76 separates the beneficial agent reservoir from the osmotic engine compartment. Extending backward from the rear surface of partition 76 is a shaft 78 with a series of detents 80. While forty detents are shown in device 61, the number of detents is not controlling and could be any number. The shaft 78 is secured to partition 76 by a rivet 82 on the forward end of the shaft. The projection 75 of each of the prongs 74 is in contact and engaged with a detent 80. The sleeve 70 and shaft 78 operate in the same manner as those of FIGS, la, lb and lc. There is present in capsule 61 a capacitance means 84, here illustrated as a free bubble of air between the partition 76 and the osmotic engine material, for providing an element of capacitance to the detent-engaging prongs 74. The capacitance means may be a resilient piece of material such as a compressible foam or it may be a pillow of air, for example. Further res-ilience is supplied by the semipermeable section 66 of the shell, which has an elastic quality of its own, adding to the overall capacitance means of the delivery device. FIG. 4 depicts in cross section an embodiment of the present invention where the delivery device 91 is a ruminal bolus. Device 91 is similar to device 11 of FIGS, la, lb and lc. It has a semipermeable capsule wall 92 which has an exit orifice 94 and which surrounds a beneficial agent reservoir 96 and an osmotically active agen compartment 98, the two compartments being separated by a partition 100. Partition 100 is attached to shaft 102 having a plurality of detents 104, one of the detents being in contact with projections 106 of four prongs 108 of sleeve 110. Device 91 additionally has a density element 112 which is dense enough to retain the device in the environment of use over a prolonged period of time. When the environment of use is the rumen of a ruminant animal, the density element is a necessary element of the delivery device. Density elements are well known in the art, and appropriate elements and materials are shown and described in U.S. Pat. Nos. 4,643,731 and 4,772,474, for example. Shaft 102 may also assist in retaining the device and act as a density element if it is made of a heavy material such as steel. Density element 112 in a presently preferred embodiment has a cavity 114 extending into the density element and sized to receive at least a portion of shaft 102 in its first, non-activated position in device 91. Cavity 114 is widened at its mouth for accepting and holding one end of sleeve 110. The widened portion of cavity 114 and the end of sleeve 110 may have threaded grooves for maintaining the two together. Alternatively, the sleeve end may be glued or otherwise attached to density element 112.

FIGS. 5a through 5e depict an embodiment of the present invention in which the delivery device 121 uses a screw-type movement of its internal parts to eject the beneficial agent. Similar to the devices of the previous figures, this device has a first, semipermeable wall 122 surrounding the lower half of the device and a second wall 123, which may be either semipermeable or impermeable, surrounding the upper half of the device and having an exit orifice 124 at the upper half, with a movable internal partition 125 dividing the interior space of the device into a beneficial agent reservoir 126 and a reservoir for the osmotically active agent 127. Affixed to the interior of the device and spanning its length is an axial shaft 128 which is threaded. The partition 125 is joined to a thread follower 129, both of which are ring-shaped and encircle the shaft. Either the thread follower 129, the partition 125, or both are threaded to complement the threads on the shaft 128, such that pressure from the lower reservoir 127 resulting from expansion of the osmotically active agent in that reservoir causes the partition 125 and thread follower 129 to rotate in screw-type manner around the shaft 128 and thereby move forward toward the exit orifice 124. The partition is sized with a close tolerance to permit this rotation to occur while retaining a seal between the partition 125 and both the shaft 128 and the internal wall of the device.

The detents 131 in this embodiment are obstacles or interruptions in the path of the screw thread which temporarily halt the rotational motion of the partition 125 and thread follower 129 while pressure builds up in the osmotically active agent. An enlarged view of these detents is seen in FIGS. 5b and 5c, which depict side and cross-sectional views of the threaded shaft. The detents 131 in these Figures are protrusions in the helical groove of the thread. In preferred embodiments, one loop or circuit of the groove contains one or more detents; in the particular embodiment shown in these Figures, the number is two per loop.

The partition 125 and thread follower 129 are shown enlarged in FIGS. 5d and 5e. The thread follower contains two resiliently mounted detent catches 132, 133. The detent catches 132, 133 engage the detents 131 in the shaft thread and immobilize the partition 125 until a sufficient pressure differential is accumulated across the partition that the resistance offered by the catches is overcome, and the catches distort sufficiently to be released from engagement with the detents. The partition 125 and thread follower 129 then rotate until the catches engage the next set of detents. Variations of the embodiment shown in FIGS. 5a through 5e which are also included within the scope of the invention are those in which the stationary element secured to the interior walls of the device is a cylindrical element threaded on the interior with detents along the thread. The cylindrical element in this case may be the wall of the device itself, and the movable partition would be a solid element inside the cylindrical element with outwardly-engaging detent catches. A further variation would retain the central shaft and encircling partition as in FIG. 5a but with the detents on the central opening of the partition rather than on the shaft. The partition in this case would be elongated to allow for a sufficiently long thread to contain a series of detents, and the central shaft would contain a resilient catch or catches at a single location along its length. In a further variation, the detents and the detent catch or catches may both be resilient, so that both would distort when the pressure differential surpasses the threshold. In a still further variation, the detents may be depressions or notches rather than protrusions, with the detent catches falling in the depressions and remaining there until the pressure forces the catches to disengage from the depressions. Still further variations will be readily apparent to those skilled in the art.

FIG. 6 is a variation on the embodiment of FIGS. 5a through 5e. in this variation, the thread follower is separated from the partition to avoid the need for the thread follower to prevent leakage between the two halves of the device. Like the other devices, this device 150 has a semi-permeable wall 151 surrounding its lower half and a wall 152, which may be either semipermeable or impermeable, surrounding its upper half, with a movable internal partition 153 and an orifice 154. A threaded shaft 155 with detents of the type included in the embodiments described above is affixed to the interior of the device at the end opposite the orifice end, and a thread follower 156 with detent-engaging catches (not shown) encircles the shaft. Connecting arms 157 extend from the thread follower and loosely encircle the base of a shaft 158 which is affixed to and protrudes from the partition. As osmotic pressure builds in the lower half of the device, force is exerted upon the underside 159 of the partition. This upward force is transmitted through the connecting arms 157 to the thread follower 156, which responds by traveling along the threads on the threaded shaft 155, which cause it to rotate, stopping at intervals due to the detents 160. The thread follower 156 and connecting arms 157 rotate together, while the other parts do not rotate. The piston thereby moves in pulses in the direction of the arrow 161.

A further variation is shown in FIG. 7. Here the device 170 contains a semi-permeable wall 171, an impermeable or semipermeable wall 172, and a partition 173 with a shaft 174 protruding from its underside identical to those of FIG. 8. The threaded shaft 175 containing the detents 176, however, is not affixed to the device walls but is instead free to move within the device. The thread follower 177 with the catches (not shown) is affixed to the internal walls of the device rather than the threaded shaft. Note that, although this is not shown in the drawing, the thread follower contains sufficient openings to allow free passage of liquid across it, so that it does not form a third compartment sealed off from the remainder of the device interior. As in the device of FIG. 6, the osmotic pressure exerts a force against the underside 178 of the partition, causing the partition to move in the direction of the arrow 179. This time, however, this force is transmitted through the connecting arms 180 to the threaded shaft 175, which responds by rotating, as do the connecting arms 180, due to the stationary thread follower 177. The detents and catches create pulsatile movement as in the device of FIG. 6.

The materials of construction of the capsules in accordance with this invention are not critical and may vary widely, provided that they are inert, capable of maintaining structural integrity and of withstanding the stresses encountered during placement of the capsule and its operation in a particular environment of use and delivering the beneficial agent, and are either semipermeable or impermeable, depending on the portion of the capsule or capsule wall in which they are used, on the particular beneficial agent to be delivered, or on the environment of use.

Semipermeable (moisture-permeable) wall materials are known in the art, and are particularly useful in the practice of this invention when the activating mechanism is an osmotically active agent. Preferred semipermeable materials are cellulosic materials, such as cellulose esters, cellulose ethers and cellulose ester- ethers. Those having a degree of substitution ("D.S."), or average number of substitutions per anhydroglucose unit at hydroxyl group positions, ranging from greater than zero up to and including 3.0, are preferred. Examples are cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di-, and tricellulose alkanylates, and mono-, di-, and tricellulose aroylates. Examples expressed in terms of D.S. ranges are cellulose acetate having a D.S. of 1.0 or less and an acetyl content of 21% or less, cellulose acetate having a D.S. of 1.0 to 2.0 and an acetyl content of 21% to 35%, and cellulose acetate having a D.S. of 2.0 to 3.0 and an acetyl content of 35% to 44.8%. Further examples are cellulose propionate with D.S. of 1.8, a propionyl content of 39.2% to 45%, and a hydroxyl content of 2.8% to 5.4%; cellulose acetate butyrate with D.S. of 1.8, an acetyl content of 13% to 15%, and a butyryl content of 34% to 39%; cellulose acetate butyrate with an acetyl content of 17% to 53%, a butyryl content of 17% to 53%, and a hydroxyl content of 0.55 to 4.7%; cellulose acetate butyrate with D.S. of 1.8, an acetyl content of 4% and a butyryl content of 51%; cellulose triacylates with D.S. of 2.9 to 3, such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, cellulose trioctanoate; cellulose diacylates with D.S. of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, and cellulose dipentanoate; and coesters of cellulose such as cellulose acetate butyrate and cellulose acetate propionate. The moisture permeability of the wall surrounding the osmotically active agent may be further controlled by the inclusion of modifiers in the wall composition. Modifiers may be selected either to decrease or to increase the moisture permeability and are known in the art. Examples of modifiers which decrease the permeability are polyacrylate, polymethacrylate, polysulfone, polyacrylic ester, polyacrylonitrile, polyacrylamide, polystyrene, polycaprolacta , polyhexamethylene adipa ide, polyhexamethylene sebacamide, polyepoxide, and polyformaldehyde. Examples of modifiers which increase the permeability are polyvinyl alcohol; poly(l,4- anhydro-?-D-mannuronic acid); polyesters derived from the condensation of a polyhydric alcohol and a polyfunctional acid whose functional groups are hydroxyl groups, carboxyl groups and the like; polysaccharides, hydroxyalkylcelluloses having molecular weights of 9,000 to 35,000; and polyalkylene glycol. Depending on its need, the modifier may be present in the wall material in an amount ranging from about 1% to about 50% by weight. Physical characteristics of the wall such as workability and flexibility, lowering of the second-order phase transition temperature and modification of the elastic modulus, may further be enhanced by the inclusion of a plasticizer. Typical plasticizers are known in the art and extend to both straight-chain and branched-chain plasticizers, cyclic plasticizers, acrylic plasticizers and heterocyclic plasticizers. Examples of classes of suitable plasticizers are phthalate, phosphate, citrate, adipate, tartrate, sebacate, succinate, glycolate, glycerolate, benzoate, myristate and sulfonamide plasticizers, including halogenated species. Particular plasticizers of interest are dialkyl phthalates such as dimethyl phthalate, dipropyl phthalate, di(2-ethylhexyl) phthalate, and diisopropyl phthalate; dicycloalkyi phthalates; diaryl phthalates; alkyl phosphates; trialkyl phosphates such as tributyl phosphate and trioctyl phosphate; aryl phosphates and triaryl phosphates such as triphenyl phosphate and tricresyl phosphate; alkyl and trialkyl citrates such as tributyl citrate and triethyl citrate; citrate esters such as acetyl triethyl citrate; alkyl adipates such as dioctyl adipate, diethyl adipate and di(2-methoxyethyl) adipate; alkyl and dialkyl tartrates such as butyl tartrate and diethyl tartrate; alkyl and dialkyl sebacates such as diethyl sebacate, dipropyl sebacate, and dinonyl sebacate; alkyl and dialkyl succinates such as diethyl succinate and dimethyl succinate; alkyl glycolates; alkyl glycerolates; glycol esters and glycerol esters such as glycerol diacetate, glycerol triacetate, glycerol monolactate diacetate and methyl phytyl ethyl glycolate. Plasticizers when included will generally comprise from about 1% to about 45% by weight of the wall composition.

The non-fluid-permeable portion of the capsule wall and the partition separating the activating mechanism compartment from the beneficial agent compartment may be constructed of any material which is inert, fluid-impermeable, and of sufficient resilience to function effectively for pulsatile delivery. The need for and degree of resilience will vary depending in part on its location in the capsule, and in part on the capsule structure, as illustrated by the differences among the drawings herein. In general, however, typical materials of construction suitable for these parts include polyolefins, condensation polymers, addition polymers, organo-silicon polymers and inorganic polymers. Specific examples are high density polyethylene, high density polypropylene, polystyrene, polycarbonate, polyamides, elastomers in general, chlorinated rubbers, styrene- butadiene rubbers, chloroprene rubbers, silicones, and glass. The shaft may be prepared from any material of suitable dimensional stability, including polymeric materials such as, but not limited to, nylon, acetals such as Delrin^®, polycarbonate, styrenes such as styrene acrylonitrile (SAN), polystyrene, ABS, polypropylene, polyethylene, polycarbonate, acrylics and polyvinyl chloride. Additional materials which may be used include steel, stainless steel, bronze, aluminum, titanium and ceramics.

The sleeve and prongs are preferably prepared from a material that exhibits a degree of resiliency. Materials which may be utilized include, but are not limited to, Delrin^®, polypropylene, polyetherimides such as Ultem^®, nylon, spring steel, spring copper and titanium.

Delivery capsules in accordance with the present invention for the pulsatile delivery of beneficial agents may be manufactured by a variety of techniques, many of which are described in the literature. In one such technique, a beneficial agent and an activating mechanism, such as an osmotically active agent or a gas-generating composition, are prepared as solid or semi-solid formulations and pressed into pellets or tablets whose dimensions correspond to the internal dimensions of the respective compartments which they will occupy in the capsule interior. With respect to the osmotically active agent, the pellets or tablets may include a hole for accommodating the sleeve and shaft. Depending on the nature of the materials used, the two agents and other solid ingredients which may be included with them may be processed prior to the formation of the pellets by such procedures as ballmilling, calendering, stirring or rollmilling to achieve a fine particle size and hence fairly uniform mixtures of each. Once the pellets have been formed, they are placed inside a pre-for ed capsule with the partition in between. The capsule may be formed from any of the wall-forming materials disclosed above by the use of a mold, with the materials applied either over the mold or inside the mold, depending on the mold configuration. Alternately, the capsule may be formed by machining the wall-forming materials to the desired shape.

In other embodiments of this invention, the beneficial agents are flowable compositions such as liquids, suspensions, slurries, pastes, soft waxes, and the like, and are poured into the capsule, either before or after the activating mechanism and the partition have been inserted. In yet other embodiments, the activating mechanism, an osmotically active agent being an example, is a flowable composition. A flowable gelled osmotically active agent is a presently preferred embodiment. Still further alternatives may include any of the wide variety of techniques known in the art for forming capsules used in the pharmaceutical industry.

The capsule orifice is also formed by conventional techniques described in the literature. Included among these methods are injection molding, mechanical drilling, laser drilling, and liquid techniques using an orifice-forming agent, such as erosion, extraction, dissolving, bursting or leaching, depending on the nature of the agent used. The capsule will contain at least one such orifice, and in most configurations, one orifice will suffice. For purposes of this invention, the term "orifice" refers to one or a plurality of orifices. The dimensions of the orifice in terms of both diameter and length will vary with the type of beneficial agent and beneficial agent formulation and the environment into which it is to be delivered. The considerations involved in determining the optimum dimensions of the orifice for any particular capsule or beneficial agent are the same as those for orifices of capsules of the prior art, and selection of the appropriate dimensions will be readily apparent to those skilled in the art.

Species which fall within the category of osmagent, that is, the non-volatile species which are soluble in water and create the osmotic gradient driving the osmotic inflow of water, are well-known in the art and vary widely. Examples are magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d- mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose, and various onosaccharides, oligosaccharides and polysaccharides such as sucrose, glucose, lactose, fructose, and dextran, as well as mixtures of any of these various species.

Species which fall within the category of osmopoly er are hydrophilic polymers that swell upon contact with water, and these are known to the art and vary widely as well. Osmopolymers may be of plant or animal origin, or synthetic. Examples are poly(hydroxyalkyl methacrylates) with molecular weight of 30,000 to 5,000,000; poly(vinylpyrrolidone) with molecular weight of 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolyte complexes; poly(vinyl alcohol) having low acetate residual, optionally crosslinked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of 200 to 30,000; a mixture of methyl cellulose, crosslinked agar and carboxymethyl cellulose; sodium carboxymethyl cellulose; a mixture of hydroxypropylmethyl cellulose and sodium carboxymethyl cellulose; polymers of N-vinyl lactams; polyoxyethylene-polyoxypropylene gels; polyoxybutylene-polyethylene block copolymer gels; carob gum; polyacrylic gels; polyester gels; polyurea gels; polyether gels; polyamide gels; polyimide gels; polypeptide gels; polyamino acid gels; polycellulosic gels; Carbopol® acidic carboxy polymers having molecular weights of 250,000 to 4,000,000; Cyanamer^® polyacrylamides; crosslinked indene-maleic anhydride polymers; Good-Rite^® polyacrylic acids having molecular weights of 80,000 to 200,000; the sodium salt of polyacrylic acid; Polyox^® polyethylene oxide polymers having molecular weights of 100,000 to 5,000,000; starch graft copolymers; and Aqua-Keeps® acrylate polymer polysaccharides. While the term "drug" appears throughout this specification, its use has been primarily for purposes of convenience. The present invention applies to the administration of beneficial agents in general, which include any physiologically or pharmacologically active substance. Included among the types of agents which meet this description are biocides, sterilization agents, nutrients, vitamins, food supplements, sex sterilants, fertility inhibitors and fertility promoters. Drug agents include drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autocoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory agents, ocular drugs, anthelmintics, antiparasitic agents, and synthetic analogs of these species.

Examples of drugs which may be delivered by devices according to this invention are prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecaxylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzphetamine hydrochloride, isoproteronol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anisindone, diphenadione erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol , allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-J-estradiol , ethinyl estradiol, ethinyl estradiol 3-methyl ether, pednisolone, 17-1- hydroxyprogesterone acetate, 19-nor-progesterones, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel , gestodene, ST-1435, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, ci etidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zo epirac, ferrous lactate, vincamine, diazepam, phenoxybenza ine, diltiazem, milrinone, captopril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin, alclofenac, mefenamic, flufena ic, difuninal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril, enalapril, captopril, ramipril, enalaprilat, famotidine, nizatidine, sucralfate, etintidine, tetratolol, melatonin, minoxidil, chlordiazepoxide, diazepam, amitriptylin, imipramine, the avermectins including ivermectin, the ionophores including tetronasin and lysocellin and laidlomycin, oxfendazole and albendazole. Further examples are proteins and peptides which include, but are not limited to, vaccines, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone, bovine somatotropin, porcine somatotropin, oxytocin, vasopressin, prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH, interferons, inter!eukins, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, vaccines, fertility inhibitors such as the prostaglandins, fertility promoters, growth factors, and human pancreas hormone releasing factor. The beneficial agent can be present in this invention in a wide variety of chemical and physical forms, such as solids, liquids and slurries. On the molecular level, the various forms may include uncharged molecules, molecular complexes, and pharmaceutically acceptable acid addition and base addition salts such as hydrochlorides, hydrobromides, sulfate, laurylate, oleate, and salicylate. For acidic compounds, salts of metals, amines or organic cations can be used. Derivatives such as esters, ethers and amides can be used. An active agent can be used alone or mixed with other active agents. The pulsatile delivery which is provided by devices in accordance with this invention may be for therapeutic purposes, nutritional purposes, preventive purposes, and a wide variety of situations in general. The environments in which the devices may be used include physiological environments within the body of a human or animal, or aqueous environments such as pools, tanks, reservoirs, moist ground, and the like serving medical, agricultural, recreational, industrial, or residential purposes. Animals to whom beneficial agents may be administered using systems of this invention include humans and other mammals and warm-blooded animals in general, avians, reptiles and fishes. Household animals, sport animals, farm animals, laboratory animals and zoo animals are included. The invention is of particular interest for application to humans and household, sport and farm animals, particularly mammals. Prominent examples other than humans are primates, sheep, goats, cattle, horses and pigs. For the administration of beneficial agents to animals, the devices of the present invention may be implanted subcutaneously or intraperitoneally or may be placed in the rumino-reticulo space of a ruminant, wherein aqueous body fluids are available to activate the osmotic engine.

The devices of this invention are also useful in environments outside of physiological or aqueous environments. For example, the devices may be used in intravenous systems (attached to an IV pump or bag or to an IV bottle, for example) for delivering beneficial agents to an animal, primarily to humans. They may also be utilized in blood oxygenators, kidney dialysis and electrophoresis. Additionally, devices of the present invention may be used in the biotechnology area, such as to deliver nutrients or growth regulating compounds to cell cultures. In such instances, activating mechanisms such as mechanical mechanisms are particularly useful.

The detent-engaging mechanism providing for pulsatile delivery from a delivery device in this invention may be activated by forces other than osmosis, which forces may be mechanical, elastomeric, vapor pressure or chemical or electrochemical in nature. For example, the detent-engaging mechanism could be coupled to a syringe on a Harvard^® syringe pump. The syringe tip of the pump is attached to the mechanism compartment of the delivery device in such manner that the mechanical force supplied by the syringe pump would substitute for the osmotic imbibition of water to supply a delivery of flow at sufficient pressure to activate the detent-engaging mechanism.

The following examples are illustrations of the practice of the invention, and are intended neither to define nor to limit the scope of the invention in any manner.

EXAMPLE 1 A delivery system in the shape of an implantable delivery device for delivering 10 pulses of an active agent and having the general configuration shown in FIG. 3 is manufactured as follows. The semipermeable membrane wall for surrounding the osmotic engine is prepared by sizing cellulose acetate butyrate (containing 51 wt% butyryl and 4 wt% acetyl) to small uniform particles. The cellulose acetate butyrate (85%) is combined with tributyl citrate (15%) and the mixture is then melted and injection-molded to give a membrane cup with an opened end for receiving an osmotically active agent formulation and for mating with the agent-containing reservoir section of the device. The membrane cup has a length of 0.75 inch (19.05 mm), a diameter of 0.25 inch (6.30 mm), and a wall thickness of 0.015 inch (0.38 mm). The impermeable reservoir for containing the active agent is prepared by drying and then melting and injection-molding polycarbonate to give a wall having an open end for receiving components and for mating with the semipermeable membrane cup and having an exit orifice in the end opposite the open end. The reservoir has a length of 1.20 inches (30.5 mm), a diameter of 0.25 inch (6.30 mm), a wall thickness over most of the length of the reservoir of 0.03 inch (0.76 mm) and at the open end of 0.015 inch (0.38 mm) for inserting into the open end of the membrane cup to give a device having smooth-sided walls when in mated arrangement. The exit orifice has an internal diameter of 0.031 inch (0.79 mm).

The sleeve is made by machining or injection-molding Delrin® into a circular U-shape with a notched portion around the top circumference of the outer wall of the U-shape, for attachment of the sleeve to the inner wall of the device. Four longitudinal slots are present equidistantly around the inner wall of the sleeve to form four flanges with prongs on the top of the inner wall, for contacting the. detents of the shaft. The length of the outer wall of the sleeve is 0.34 inch (8.64 mm) and the length of the inner wall is 0.43 inch (10.92 mm). The shaft with detents is machined or molded from Delrin^®. The shaft diameter is 0.040 inch (1.02 mm) and the diameter of each detent is 0.060 inch (1.52 mm). There are 10 detents, with the spacing between detents being 0.057 inch (1.45 mm) and the angle of the detent surface being 10°. A rivet-shaped extension is at the top end of the shaft, for attachment to a partition.

The partition is prepared by injection-molding Santoprene® (a polypropylene/ethylene-propylene-diene monomer blend), the partition having a length of 0.186 inch (4.72 mm) and a diameter of 0.192 inch (4.88 mm) and being molded around and enclosing the rivet extension of the shaft.

The osmotic driving agent is prepared by mixing together 50 wt% sodium chloride, 1 wt% sodium carboxymethylcellulose and 49 wt% water. Alternatively, the osmotic driving agent is prepared by mixing together 95 wt% sodium chloride and 5 wt% sodium carboxymethylcellulose, which is then compressed into tablets of suitable size and configuration.

The delivery device is assembled by placing the partition with attached shaft into the impermeable agent reservoir section. The sleeve is then glued or otherwise affixed to the open end of the agent reservoir wall, with the prongs facing into the reservoir. The partition and shaft are arranged so that the prongs of the sleeve are situated at the first detent, next to the partition. The osmotic driving means is placed in the semipermeable membrane cup, which is then joined at its opened end with the open end of the reservoir by partially inserting the reservoir into the cup. Adhesive such as moisture-cured cyanoacrylic is placed onto the remaining exposed surface of the ends and the two members are then fully inserted to give a sealed delivery system. An active agent formulation (280 μl) is then injected into the reservoir through the exit orifice and the orifice is sealed by dipping it quickly into melted wax, which is then allowed to cool . EXAMPLE 2 . A delivery device substantially similar to that of Example 1 is manufactured, except that it includes a shaft having 20 detents positioned equidistantly. The resulting device delivers 20 pulses of active agent.

EXAMPLE 3 A delivery system in the shape of a ruminal bolus and having the general configuration shown in FIG. 4 is manufactured as follows. A semipermeable membrane cup is prepared by blending together cellulose acetate butyrate, cellulose acetate, triethyl citrate, tributyl citrate and polyethylene glycol 400 and then melting and injection-molding a cup 96 mm (3.8 in.) in length, having a 25 mm (1.0 in.) outside diameter and a 75 mils thick wall. A step on the inside wall is present 34 mm from the open end of the cup, so that the wall thickness from this point to the open end is 55 mils.

A stainless steel shaft is made, having 10 detents and a rivet- shaped extension on the top end of the shaft.

A partition is prepared by injection-molding Santoprene®, the partition having a length of 10 mm (0.39 in.) and a diameter of 21.6 mm (0.85 in., corresponding to the inside diameter of the membrane cup) and being molded around the rivet extension of the shaft.

A sleeve having four prongs for contacting the detents of the shaft and having threaded grooves on its base is manufactured by injection molding Delrin^®. A stainless steel density element having an outside diameter corresponding to the inside diameter of the membrane cup at its opened end is manufactured, having in addition a cavity extending through its center of sufficient length and diameter for receiving a portion of the shaft in its first, non-activated position in the delivery device. The cavity is widened at its top and has threaded grooves in the widened portion for accepting the threaded grooves of the sleeve.

The device is assembled by first placing an active agent formulation into the membrane cup. The prongs of the sleeve are placed onto the first detent of the shaft, next to the partition. The partition and shaft, with attached sleeve, is placed into the cup, the partition being in contact with the agent formulation. An osmotic formulation having a composition of 61 wt% sodium chloride, 1 wt% sodium carboxymethylcellulose and 38 wt% water is then placed into the cup, to the level of the step in the cup wall. The density element is threaded onto the sleeve so that the density element is seated next to the osmotic formulation and against the step in the cup wall. The open end of the cup is then heated and the ends are crimped down around the density element. Finally, a 50 mil exit passageway is drilled into the end of the device opposite from the density element to provide the finished delivery device.

EXAMPLE 4 A test was performed using a delivery device of the general configuration shown in FIG. la, but having a mechanical activating mechanism rather than an osmotic activating mechanism. This was accomplished by, first, not placing an osmotically active agent formulation into the activating mechanism compartment of the capsule device. An inlet was created at the base end of the capsule opposite from the exit orifice, which capsule was made of an impermeable material such as polycarbonate rather than of a semipermeable material. Into the inlet was inserted the tip of a syringe from a Harvard^® syringe pump. Additionally, the sleeve was not U-shaped but rather had a ridge extending circumferentially around the outside of the sleeve wall and of the same diameter as the inner wall of the device. The sleeve was attached to the wall of the device by means of this ridge. For purposes of the test, silicone oil was placed in the beneficial agent formulation compartment.

The test was conducted as follows. The Harvard syringe pump was advanced at a steady rate of 0.0494 mL/min to deliver water into the space behind the partition. The silicone oil delivered through the exit orifice of the device was collected and measured continuously on an electronic pan balance. The results are shown in FIG. 8, which is a plot of mass delivered from the beneficial agent compartment vs. time. The plot illustrates that the partition remained at rest for intervals of approximately three minutes between forward advances, and that these advances occurred in a repetitive and substantially unchanging manner, and that upon each forward advance of the partition, the device delivered approximately 0.18 grams of fluid/oil. This demonstrates that the partition moved in a pulsatile manner driven solely by the force provided by the fluid (water) delivered by the syringe pump.

EXAMPLE 5

A test was performed on a device substantially similar to the device described in Example 4, except that the activating mechanism was provided by osmotic action by means of a cellulose acetate butyrate membrane cup containing an osmotically active agent formulation (50 wt% sodium chloride/1 wt% sodium carboxymethylcellulose/49 wt% water gel) releasably attached, by means of a detachable stainless steel body, to the portion of the device containing the beneficial agent formulation, the sleeve, the shaft and the partition. The stainless steel body had a center passageway so that pressure increases provided by fluid flow through the membrane cup and to the osmotically active agent were transmitted to the partition. There were four prongs on the end of the sleeve evenly spaced around the diameter of the sleeve and in contact with a detent. The beneficial agent compartment portion of the device was composed of polycarbonate, the sleeve and shaft were composed of Delrin^®, and the partition was composed of butyl rubber (device of FIG. 9a) or silicone rubber (device of FIG. 9b). For the device of FIG. 9a, there were ten detents on the shaft, with a spacing of 0.070 in. (1.78 mm); for the device of FIG. 9b, there were ten detents, with a spacing of 0.058 in. (1.46 mm). For purposes of the test, silicone oil was placed in the beneficial agent formulation compartment. In each of the devices, a 1.4 cc volume of air was present between the osmotically active agent and the partition. The air acts as a capacitance means. The test was conducted by partially submerging the test device in a 50°C water bath so that the membrane cup was completely surrounded by water. The silicone oil delivered from the device was collected and measured continuously on an electronic pan balance. The results of two different tests are shown in FIGS. 9a and 9b. EXAMPLE 6 . Following the general procedures of Example 1, a device having the general configuration shown in FIG. 3 was manufactured for the delivery of porcine somatotropin. The length of the device was 2.765 inches (70.2 mm).

The semipermeable membrane wall or cup was prepared out of cellulose acetate and with an outside diameter of 0.31 inch (7.9 mm) tapering to 0.296 inch (7.5 mm) and a wall thickness of 0.023 inch (0.6 mm). The impermeable reservoir for containing the porcine somatotropin formulation was prepared out of polymethyl methacrylate, having a length of 1.975 inches (50.2 mm), an outside diameter of 0.35 inch (8.9 mm), a wall thickness of 0.031 inch (0.8 mm).

The sleeve or collet was made by machining polyetherimide resin (Ultem®). Four longitudinal slots were present equidistantly around the sleeve to form four flanged prongs, the length of each prong being 0.245 inch (6.2 mm). The sleeve outer diameter was 0.14 inch (3.6 mm) and the wall thickness was 0.015 inch (0.8 mm).

The shaft with detents was machined from Delrin. The outside diameter of the shaft was 0.074 inch (1.9 mm) and there were 17 detents, with the spacing between detents being 0.054 inch (1.4 mm). The partition was made of compression-molded butyl rubber and was joined to the rivet of the shaft after molding.

The osmotic driving agent was prepared by mixing together 55 wt% sodium chloride, 1 wt% sodium carboxymethylcellulose and 44 wt% water to form a flowable gel formulation. The porcine somatotropin formulation was 7.6 wt% active porcine somatotropin in a phosphate/glycerol/Tween 80 formulation.

The device was assembled following the procedures of Example 5, making sure that a 0.4 cc volume of air was present in the driving agent reservoir to act as a capacitance means.

The device was tested following the procedures of Example 5, and the amount of porcine somatotropin delivered from the device, in a pulsatile manner, is shown in FIG. 10. The foregoing is offered primarily for purposes of illustration. It will be readily apparent to those skilled in the art that the number and arrangement of parts, materials of construction, dimensions, and other parameters of the system may be further modified or substituted in various ways without departing from the spirit and scope of the invention.

Claims

WHAT IS CLAIMED IS:

1. A delivery device for placement in an environment of use for the pulsatile delivery of a beneficial agent to said environment, said device comprising: an enclosure having a longitudinal axis, first and second ends, an inner wall surface and an orifice at said first end; a partition dividing the interior of said enclosure into a first compartment for retaining a beneficial agent and a second compartment for retaining an activating mechanism, said first and second compartments being adjacent to said first and second ends, respectively, said partition being capable of moving longitudinally within said enclosure; a pair of guide members retained within said enclosure, one guide member of said pair consisting of a shaft parallel to said longitudinal axis, and the other guide member of said pair consisting of a shaft-engaging member engaging said shaft, one of said guide members being affixed to said enclosure and being defined as a stationary guide member, and the other being affixed to said partition and being defined as a mobile guide member; one of said guide members having a plurality of detents thereon, and the other having at least one detent-engaging member positioned to resiliently engage said detents, each said detent thereby maintaining said mobile guide member immobile relative to said stationary guide member until a threshold pressure differential between said first and second compartments is exceeded.

2. A delivery device in accordance with claim 1 in which said plurality of detents are affixed to said shaft and said at least one detent-engaging member is affixed to said shaft-engaging member.

3. A delivery device in accordance with claim 1 in which said stationary guide member is said shaft and said mobile guide member is said shaft-engaging member.

4. A delivery device in accordance with claim 1 in which said shaft is affixed to said partition and said shaft-engaging member is affixed to said enclosure.

5. A delivery device in accordance with claim 1 in which said shaft-engaging member is a sleeve which receives said shaft at one end and contains at least one longitudinal slot at said end, with said at least one detent-engaging member adjacent to said at least one longitudinal slot.

6. A delivery device in accordance with claim 1 in which said shaft-engaging member is a sleeve which receives said shaft at one end and terminates at said end in at least two prongs, each said prong terminating in one said detent-engaging member.

7. A delivery device in accordance with claim 1 in which said shaft includes at least three said detents.

8. A delivery device in accordance with claim 1 in which said shaft includes at least ten said detents.

9. A delivery device in accordance with claim 1 in which said detents are spaced apart from each other along said longitudinal axis at intervals such that advancement of said at least one detent- engaging member between adjacent detents is achieved by linear movement of said mobile guide member along said longitudinal axis relative to said stationary guide member.

10. A delivery device in accordance with claim 9 in which said detents are formed in said shaft, and said shaft is said mobile guide member.

11. A delivery device in accordance with claim 9 in which said detents are formed in said shaft, and said shaft is said stationary guide member.

12. A delivery device in accordance with claim 1 in which complementary helical threads are formed in said mobile and stationary guide members such that movement of said mobile guide member relative to said stationary guide member is by screw-like rotation of said mobile guide member along said complementary helical threads; and said detents are formed along one of said complementary helical threads while said detent-engaging members are formed in the other of said complementary helical threads such that advancement of said at least one detent-engaging member between adjacent detents is achieved by screw-like motion of said mobile guide member relative to said stationary guide member.

13. A delivery device in accordance with claim 12 in which said detents are spaced apart at intervals less than or equal to one revolution of said complementary helical threads.

14. A delivery device in accordance with claim 12 in which said detents are formed in said shaft, and said shaft-engaging member is a ring encircling said shaft.

15. A delivery device in accordance with claim 12 in which said detents are formed in said shaft, said shaft is said stationary member, and said shaft-engaging member is a ring encircling said shaft.

16. A delivery device in accordance with claim 1 in which said shaft-engaging member and said enclosure are each substantially circular in cross section.

17. A delivery device in accordance with claim 1 in which said threshold pressure differential is from about 0.01 to about 100 pounds force per inch.

18. A delivery device in accordance with claim 1 in which said threshold pressure differential is from about 0.5 to about 15 pounds force per inch.

19. A delivery device in accordance with claim 1 in which said enclosure, said detents and said at least one detent-engaging member are constructed such that when said activating mechanism is activated, such activation causes said at least one detent-engaging member to advance from one of said detents to the next of said detents.

20. A delivery device in accordance with claim 19 wherein said activation causes said at least one detent-engaging member to advance from one of said detents to the next detent at intervals of at least 2 minutes.

21. A delivery device in accordance with claim 19 wherein said activation causes said at least one detent-engaging member to advance from one of said detents to the next detent at intervals of from about 2 hours to about 120 days.

22. A delivery device in accordance with claim 21 in which said intervals are from about 6 hours to about 20 days.

23. A delivery device in accordance with claim 1 wherein said detents are spaced at equal intervals on the guide member.

24. A delivery device in accordance with claim 1 wherein said detents are spaced at unequal intervals on the guide member.

25. A delivery device in accordance with claim 1 wherein said device further comprises a density element.

26. A delivery device in accordance with claim 1 in which said activating mechanism is selected from the group consisting of an osmotic engine, a thermal system, a mechanical system, a system dependent on vapor pressure of fluid, a system dependent on chemical or electrochemical reactions, an elastomeric system, a spring-loaded chamber or piston, and a system dependent on gravity.

27. A delivery device in accordance with claim 1 in which said activating mechanism is an osmotic engine which is used to activate said at least one detent-engaging member.

28. A delivery device in accordance with claim 27 in which said environment of use is an aqueous environment, at least a portion of said enclosure of said device adjacent to said second end is permeable to moisture, and said activating mechanism is an osmotic engine.

29. A delivery device in accordance with claim 1 in which said activating mechanism is a mechanical system which is used to activate said at least one detent-engaging member.

30. A delivery device in accordance with claim 1 in which said activating mechanism is a system which is dependent on gravity which is used to activate said at least one detent-engaging member.

31. An osmotically driven device for placement in an aqueous environment for the pulsatile delivery of a beneficial agent to said environment, said device comprising: an enclosure having a longitudinal axis, first and second ends, an inner wall surface and an orifice at said first end, at least a portion of said enclosure adjacent to said second end being permeable to moisture; a partition dividing the interior of said enclosure into a first compartment for retaining a beneficial agent and a second compartment for retaining an osmotically active agent or mixture of osmotically active agents, said first and second compartments being adjacent to said first and second ends, respectively, said partition being capable of moving longitudinally within said enclosure; a pair of guide members retained within said enclosure, one guide member of said pair consisting of a shaft parallel to said longitudinal axis, and the other guide member of said pair consisting of a shaft-engaging member engaging said shaft, one of said guide members being affixed to said enclosure and being defined as a stationary guide member, and the other being affixed to said partition and being defined as a mobile guide member; one of said guide members having a plurality of detents 5 thereon, and the other having at least one detent-engaging member positioned to resiliently engage said detents, each said detent thereby maintaining said mobile guide member immobile relative to said stationary guide member until a threshold pressure differential between said first and second o compartments is exceeded.

32. A method for providing delivery of a beneficial agent in a pulsatile manner to an environment of use, said method comprising:

1) placing in said environment a delivery device, said s device comprising: an enclosure having a longitudinal axis, first and second ends, an inner wall surface and an orifice at said first end; a partition dividing the interior of said enclosure 0 into a first compartment for retaining a beneficial agent and a second compartment for retaining an activating mechanism, said first and second compartments being adjacent to said first and second ends, respectively, said partition being capable of moving longitudinally 5 within said enclosure; a pair of guide members retained within said enclosure, one guide member of said pair consisting of a shaft parallel to said longitudinal axis, and the other guide member of said pair consisting of a shaft-engaging o member engaging said shaft, one of said guide members being affixed to said enclosure and being defined as a stationary guide member, and the other being affixed to said partition and being defined as a mobile guide member; 5 one of said guide members having a plurality of detents thereon, and the other having at least one detent-engaging member positioned to resiliently engage said detents, each said detent thereby maintaining said mobile guide member immobile relative to said stationary guide member until a threshold pressure differential between said first and second compartments is exceeded; and

2) activating said activating mechanism in said device to cause said at least one detent-engaging member to advance in succession from one said detent to the next.

33. A method in accordance with claim 32 wherein said environment of use is an aqueous environment, at least a portion of said enclosure of said device adjacent to said second end is permeable to moisture, said activating mechanism is an osmotically active agent or a mixture of osmotically active agents, and said activating mechanism is activated by allowing said device to imbibe fluid from said aqueous environment through said moisture-permeable enclosure to activate said osmotically active agent or agents.

34. A delivery device in accordance with claim 1 which further comprises a capacitance means in said second compartment.

35. An osmotically driven device in accordance with claim

31 which further comprises a capacitance means in said second compartment.

36. A method in accordance with claim 32 wherein said delivery device further comprises a capacitance means in said second compartment.