 |
Description  |
|
|
FIELD OF THE INVENTION
The present invention is related to the protracted pulsatile delivery of an
active agent. More particularly, it is related to osmotically-activated
devices for dispensing active agents to a biological environment of use
for an extended or protracted period of time following an initial delay.
BACKGROUND OF THE INVENTION
Osmotic dispensing devices for delivery of therapeutically active agents
are well known in the art. Such devices use an expansion means to deliver
an agent to an environment of use over a period of hours, days or months.
The expansion means absorbs liquid, expands, and acts to drive out
beneficial agent formulation from the interior of the device in a
controlled, usually constant manner. The osmotic expansion means is used
to controllably, usually relatively slowly, and over a period of time,
deliver the agent. Thus, these devices are not generally used to delay the
initial release of the agent.
The delay of the initial release of an agent has primarily been previously
effected by coating the agent or a formulation containing the agent with a
dissolvable or bioerodible coating layer, such as gelatin, which coating
dissolves or erodes in the environment of use to then make the agent
available. Delayed initial release has also been provided by dispersing
the agent in a dissolvable or erodible matrix. However, such systems are
often unreliable and release cannot be controlled with great accuracy due
to the variability and relatively uncontrollable nature of erosion and
dissolution.
Therefore, there remains a continuing need for improved methods and systems
for providing a delayed initial delivery of an active agent to an
environment of use that are reliable and that can be programmed to deliver
the agent after a particular interval with increased accuracy. In
addition, there is a need for systems which provide a protracted pulse
delivery of an agent following a delayed startup, which delivery, once
begun, can be extended and otherwise controlled.
SUMMARY OF THE INVENTION
The present invention is directed to a fluid-imbibing dispensing device for
the extended or protracted delivery of an active agent following an
initially delayed startup of the delivery to a fluid environment of use.
The dispenser comprises a housing having a first wall section and a second
wall section in reversibly sliding telescopic arrangement with each other,
which housing maintains its integrity in the environment of use; an
internal compartment surrounded and defined by the housing; at least one
active agent formulation in a portion of the compartment defined by the
first wall section; at least one opening in the side wall of the first
wall section, each opening extending longitudinally along a portion of the
side wall of the first wall section, for providing communication between
the active agent formulation and the environment; expansion means within a
portion of the compartment defined by the second wall section, for
separating apart the first and second wall sections of the housing after
exposure to the environment of use; and, optionally, a partition layer or
push plate between the active agent formulation and the expansion means.
The invention also is directed to a method for delaying the initial
delivery of an active agent to a fluid environment of use, after which
delay the active agent is delivered to the environment over an extended
period and in a protracted manner, the method comprising placing the
dispensing device of the invention into the environment of use, allowing
fluid to be imbibed through at least a portion of the housing of the
dispensing device for causing the expansion means to expand and exert
pressure on the slidably connected first and second wall sections to push
apart and separate the two wall sections to deliver an active agent
formulation through the opening or plurality of openings in the first wall
section to the environment after an initially delayed period of time. That
is, as the two wall sections are being pushed apart, an increasing area of
the opening or openings becomes exposed to the fluid environment, allowing
the active agent formulation to leach out of the device through the
openings to provide a protracted pulse of agent delivery.
During the initial delay period in the environment, the volume of that
portion of the compartment containing the active agent is kept constant;
therefore, there is a negligible pressure gradient between the environment
and the interior of the agent-containing compartment. As a result, net
flow of the environmental fluid driven by the pressure to enter the
agent-containing compartment is minimal, so that the active agent is not
contaminated or diluted prior to commencement of delivery.
DESCRIPTION OF THE DRAWINGS
The drawings are not drawn to scale, but are set forth to illustrate
various embodiments of the invention. Like numbers refer to like
structures.
FIG. 1 is a cross-sectional view of one embodiment of the present
invention, the device being in closed or prepared form prior to placement
in the environment of use.
FIG. 2 is the device of FIG. 1 in operation after activation by placement
in the environment of use, showing the device partially opened to release
the active agent formulation to the environment.
FIG. 3 is an exterior side view of the device of FIG. 2.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a device which is useful for the initial
delayed delivery of an active agent formulation to a fluid environment of
use, the delivery of the agent formulation from the dispensing device,
once begun, being continued over an extended period; that is, all of the
agent is not released into the environment at one time. By "extended
period of time" is meant a protracted time period such as for one hour, up
to several hours, days, weeks or months.
As used herein, the terms "therapeutically effective" amount or rate refer
to the amount or rate of the active agent needed to effect the desired
therapeutic, often beneficial, result.
The dispensing devices of the invention find use, for example, in humans or
other animals. The environment of use is a fluid environment and can
comprise the stomach, the intestinal tract, or a body cavity such as the
peritoneum or vagina. A single dispensing device or several dispensing
devices can be administered to a subject during a therapeutic program.
FIG. 1 depicts in cross-sectional view a presently preferred embodiment of
the delivery device according to the present invention. The device is
shown in closed or prepared form prior to placement in the environment of
use. Dispensing device 1 comprises a housing 12 formed of a first wall
section 14 and a second wall section 16. First wall section 14 and second
wall section 16 are in reversibly sliding telescopic arrangement with each
other. Housing 12 surrounds and defines an internal compartment 18. First
wall section 14 surrounds that portion of internal compartment 18 that
contains an active agent formulation 20 (not shown in FIG. 1). Second wall
section 16 surrounds that portion of internal compartment 18 that contains
an expansion means 22 for expanding and for occupying space in compartment
18. Second wall section 16 also contains a partition layer or push plate
24, which push plate 24 is positioned between the agent formulation 20 and
the expansion means 22. Push plate 24, in a presently preferred
embodiment, comprises a composition that is substantially impermeable to
the passage of fluid, and it serves to restrict the passage of fluid
present in the expansion means into that area of compartment 18 that
contains the agent formulation. It operates to essentially maintain the
integrity of the active agent formulation and the expansion means layer.
Additionally, and importantly, push plate 24 acts to insure that the
expanding driving force generated by the expansion means 22 is applied
directly against the first wall section 14 to effect the separation of the
two wall sections. Thus, push plate 24 must be of sufficient strength,
thickness and rigidity to transfer the driving force against first wall
section 14.
Each of first wall section 14 and second wall section 16 has an open end,
the open end of first wall section 14 being adapted to fit within the open
end of second wall section 16. The two wall sections at their open ends
are close in size and they form a friction fit therebetween. The friction
generated is sufficient to maintain the two wall sections together prior
to activation of the expansion means but not so great as to keep the two
wall sections from sliding apart once an expanding driving force is
exerted. Where additional friction is desired, protrusions may be present
at or near the open end of the first wall section for providing further
friction between the two wall sections. First wall section 14 and second
wall section 16 can be telescoped completely into a closed external walled
position. The bottom edge of the open end of first wall section 14
provides a platform or ridge 28 protruding into compartment 18. Ridge 28
is adapted to receive the driving force of the expansion means 22, via the
push plate 24, to effect the separation of the two wall sections.
First wall section 14 has a plurality of openings 30, shown in device 1 as
four elongated openings 30a, 3Ob, 30c and 30d, which extend longitudinally
along a portion of the side wall of the first wall section. According to
the invention, the number of openings is variable, and may be selected
from, generally, one to ten openings, or more, to moderate the rate of
leaching of agent from the device. In a presently preferred embodiment,
the number of openings 30 is from two to ten, depending on the protraction
of release that is desired. The openings can have any shape, but in a
preferred embodiment the shape is an elongated rectangle or ellipse.
Alternatively, each opening 30 may consist of a series of smaller
openings, such as for example squares, circles, triangles, rectangles or
ellipses, extending longitudinally along the side wall of the first wall
section 14.
In operation, as the expansion means 22 absorbs and imbibes fluid through
second wall section 16 from the environment of use, it expands and pushes
against push plate 24, causing the push plate to slide inside compartment
18. Push plate 24 moves toward and contacts ridge 28, pushing against
ridge 28 and thus against first wall section 14 to cause the first wall
section to slide apart from second wall section 16 as the expansion means
22 continues to expand. As the two wall sections are pushed apart, the
openings 30 begin to become progressively exposed to the environment,
causing the active agent formulation 20 to be exposed and released to the
environment of use via the exposed portions of the openings 30, as
illustrated in FIGS. 2 and 3.
FIGS. 2 and 3 illustrate the dispensing device 1 of FIG. 1 in operation
after activation of the device by placement in the environment of use.
FIGS. 2 and 3 show device 1 partially opened to release a portion of the
active agent formulation 20 to the environment (FIG. 2 as a longitudinal
cross-sectional view and FIG. 3 as a longitudinal exterior view). As
illustrated in FIG. 2, first wall section 14 has been partially separated
from second wall section 16 to expose a portion of the openings 30,
separation having occurred by the expanding driving force of the expansion
means 22, which has expanded in size as a result of imbibing fluid from
the environment. The arrows in FIG. 2 indicate the exiting of the active
agent formulation 20 from internal compartment 18 through the exposed
portions of the openings 30 in first wall section 14, which are now in
communication with the environment.
The delivery profile of the active agent from the device of the present
invention can be determined by varying the characteristics of the openings
30, such as by varying the number, size and/or placement of the openings.
For example, the time period for the initial delay of startup of delivery
can be set by the initial distance of the openings from the open end of
the second wall section 16, the initial distance illustrated as distance
32 in FIG. 1. The amount of active agent released over time can be
determined by the length of the openings, by the number of openings
present in the wall, by the width of the openings, or by a combination of
these.
First wall section 14 may comprise a composition that is semipermeable,
that is, it is permeable to fluid but impermeable to active agent and
other ingredients contained in dispensing device 1, or it may,
alternatively, comprise a composition that is impermeable to the exchange
of fluid, agent and other ingredients. When an active agent or an active
agent dosage form is sensitive to fluid from an exterior fluid present in
the environment of use, it is preferred that first wall section 14 be
substantially impermeable to the ingress of the external fluid to serve as
a means for substantially protecting the agent or dosage form.
Because expansion means 22 operates by the imbibition of external fluid,
second wall section 16 in at least a portion that is initially adjacent to
expansion means 22 must be semipermeable; that is, it is permeable to the
passage of fluid while being substantially impermeable to the passage of
other ingredients contained in dispensing device 1. In one embodiment,
second wall section 16 is semipermeable in its entirety. In another
embodiment, second wall section 16 is composed of an impermeable material
in that portion that initially contacts the openings 30, in order to
protect the active agent from exposure to fluid from the fluid environment
until such time as openings 30 themselves are exposed to the environment.
Wall sections 14 and 16 optionally comprise additional ingredients such as,
for example, a plasticizer. Impermeable and semipermeable compositions
suitable for use in wall sections 14 or 16, as well as suitable additives,
are known in the art, examples of which are disclosed in U.S. Pat. No.
4,874,388, the entire disclosure of which is incorporated herein by
reference.
Housing 12, comprising wall sections 14 and 16, is nontoxic, biologically
inert, nonallergenic and nonirritating to body tissue, and it maintains
its physical and chemical integrity; that is, housing 12 does not erode or
degrade in the environment of use during the dispensing period. It is
within the scope of the invention that the housing be insoluble only
during the period of intended use and can thereafter dissolve away in the
environment of the device. Thus, a dispenser is here contemplated which is
unaffected by its environment, solubility-wise, at the situs of use or
which, alternatively, is only slightly soluble during the period of
intended use, such that once its active agent content has been removed it
will then dissolve or erode away leaving no objectionable residue or empty
container at the situs of use.
The expansion means or expandable driving means 22, operable for separating
the first and second wall sections to release the active agent from the
dispensing device of the invention, is nontoxic, nonallergenic and
biologically inert. Expansion means 22 comprises, in one presently
preferred embodiment, an osmopolymer. The osmopolymers interact with water
and aqueous biological fluids and swell or expand to an equilibrium state.
The osmopolymers exhibit the ability to swell in fluid and to retain a
significant portion of the imbibed and absorbed fluid within the polymer
structure. The expansion means 22 in another preferred embodiment
comprises an osmagent. The osmagents are known also as osmotically
effective solutes and they are also known as osmotically effective
compounds. The osmagents that can be used for the purpose of this
invention include inorganic and organic compounds that exhibit an osmotic
pressure gradient across a semipermeable, i.e. a fluid-permeable, wall.
The expansion means 22 in yet another preferred embodiment comprises an
osmagent dispersed within an osmopolymer. The expansion means 22 can
comprise a tablet or a layer, or a plurality of tablets or layers, or it
can be pressed into second wall section 16. The osmagent or osmopolymer
can be in any suitable form such as particles, crystals, pellets,
granules, and the like, when pressed into a tablet layer and into wall
section 16. Osmagents and osmopolymers are known to the art and are
described in, for example, U.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893,
4,327,725 and 4,612,008.
Push plate 24, present in certain embodiments of the invention between the
active agent formulation and the expansion means, is a means for
transmitting the force generated by the expansion means against the first
wall section 14, for maintaining the separate identity of the active agent
formulation and the expansion means, and for substantially restricting the
passage of fluid between the active agent formulation and the expansion
means. Representative materials useful as a partition layer or push plate
24 are known to the art in, for example, U.S. Pat. No. 4,874,388.
The term "active agent formulation", as used herein, comprises the active
agent to be delivered, as a liquid, solid, semisolid or thermosensitive
composition, generally in a carrier substance and with or without
additional inert ingredients. The term may additionally include dosage
forms comprising the active agent which are capable of maintaining their
physical configuration and chemical integrity while housed within the
dispenser. These include, without limitation, tablets with or without a
density element; matrix tablets; spheres; tiny pills; pellets and
elongated tablets; capsules; elementary osmotic pumps, such as those
described in U.S. Pat. No. 3,845,770; miniosmotic pumps, such as those
described in U.S. Pat. Nos. 3,995,631, 4,034,756 and 4,111,202; and
multichamber osmotic systems referred to as push-pull and push-melt
osmotic pumps, such as those described in U.S. Pat. Nos. 4,320,759 and
4,449,983; all the above patents of which are incorporated herein by
reference.
The pharmaceutically acceptable carrier useful herein may comprise more
than one ingredient, such as, for example, a buffer, a viscosity
regulating vehicle, a surfactant, dyes, a permeation enhancer, proteinase
inhibitors, or other formulation ingredients and additives, as are known
in the art. The carrier may contain more than one active agent. The active
agent formulation can erode or disintegrate and can be in the form of a
wax formulation, solid core or tablet, for example. The formulation can
immediately dissolve upon exposure to fluid or it may erode slowly with or
without the presence of excipients for controlling erosion.
The active agent formulation can be designed in a multitude of ways to
provide a specific drug delivery profile. One embodiment may comprise a
formulation that contains a biologically acceptable solid surfactant which
is capable of slow dispersion in the environmental fluid. In another
embodiment, the formulation may contain a fluid-insoluble wax and a
surfactant so that the formulation is susceptable to erosion in the
environment. In still another embodiment, the formulation may be
effervescent and provide drug delivery in a finely dispersed form. This is
accomplished by the addition of a solid basic compound capable of evolving
carbon dioxide in the presence of an acid in the environment of use.
Suitable basic compounds are disclosed in U.S. Pat. No. 4,265,874. In a
further embodiment, the formulation may include an osmotic agent or
solute, such as those described above with reference to the expansion
means 22, so that when the formulation comes into contact with the
environmental fluid, it immediately dissolves. In yet another embodiment,
the agent formulation can be comprised of an agent and a thermoresponsive
composition. In this manner, the formulation would exhibit solid-like
properties at room temperature of 21.degree. C. and within a few degrees
Celsius thereof, and would have a melting point that approximates
mammalian body temperatures of 37.degree. C. and within a few degrees
Celsius thereof. The term "thermoresponsive" as used herein in a preferred
embodiment denotes the physical-chemical property of an agent carrier
composition to exhibit solid, or solid-like properties at temperatures up
to 31.degree. C and become fluid, semisolid or viscous when disturbed by
heat at temperatures from 31.degree. C., usually in the range of
31.degree. C. to 45.degree. C. Suitable materials useful as active agent
carriers and excipients are known in the art and are disclosed in U.S.
Pat. Nos. 4,595,583 and 4,874,388, for example.
The terms "active agent" and "drug" are used interchangeably herein and
refer to an agent, drug, compound, composition of matter or mixture
thereof which provides some therapeutic, often beneficial, effect. This
includes pesticides, herbicides, germicides, biocides, algicides,
rodenticides, fungicides, insecticides, antioxidants, plant growth
promoters, plant growth inhibitors, preservatives, antipreservatives,
disinfectants, sterilization agents, catalysts, chemical reactants,
fermentation agents, foods, food supplements, nutrients, cosmetics, drugs,
vitamins, sex sterilants, fertility inhibitors, fertility promoters,
microorganism attenuators and other agents that benefit the environment of
use. As used herein, the terms further include any physiologically or
pharmacologically active substance that produces a localized or systemic
effect or effects in animals, including warm blooded mammals, humans and
primates; avians; domestic household or farm animals such as cats, dogs,
sheep, goats, cattle, horses and pigs; laboratory animals such as mice,
rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like.
The active drug that can be delivered includes inorganic and organic
compounds, including, without limi | | |
