Drug delivery device which can be retained in the stomach for a controlled period of time

A drug delivery device retained in the stomach comprising a planar figure made from an erodible polymer that may release a drug associated therewith over a controlled, predictable and extended period of time.

DESCRIPTION OF THE PRIOR ART 
Numerous patents and publications have described devices which can be 
retained in the stomach for extended periods of time. The prior art can be 
categorically described according to the technologies listed below: 
1. Floating devices 
2. Swelling devices 
3. Inflating balloons and 
4. For ruminant animals--various shapes. There follows a discussion of each 
of the above technologies which demonstrates the technological advancement 
of the invention over the prior art: 
(1) Michaels et al (Alza Corporation), U.S. Pat. No. 3,901,232, describe a 
device which contains a drug delivery compartment attached to an envelope 
which is contained within an erodible capsule. Upon ingestion, the capsule 
dissolves and a liquid contained in the envelope vaporizes and swells the 
envelope to provide a means of retention by flotation within the desired 
body cavity e.g. the stomach. 
S. Watanabe et al, U.S. Pat. No. 3,976,764 teach the use of a hollow or low 
density core surrounded by polymeric materials containing drug(s). The 
device floats in the stomach and releases said drug over an extended 
period of time. 
Sheth and Tossounian, U.S. Pat. Nos. 4,140,755 and 4,167,558 describe the 
use of a tablet which is hydrodynamically balanced to be buoyant under 
gastric conditions thereby remaining in the stomach for an extended period 
of time. 
All of the references in this category function on the basis of floatation 
or buoyancy and do not teach the use of size to retain them in the 
stomach. 
(2) Johnson et al, U.S. Pat. No. 3,574,820 teach the use of tablets or 
capsules containing a reaction product of gelatin and 
N-acetyl-homocysteine thiolactone as a component of an oral dosage form 
small enough to be swallowed but which swells in the stomach to become too 
large to pass through the pylorus. 
Banker, U.S. Pat. No. 261,242 describes the use of a swellable polymer 
(e.g. Gantrez) coated on the outside of tablets or capsules such that the 
coating swells under gastric conditions. 
Mamajek and Moyer, U.S. Pat. No. 4,207,890 teach the use of an expandable 
envelope containing a drug and an agent which expands when gastric fluid 
permeates through the envelope. The device enlarges and is retained in the 
stomach for an extended period. There is no teaching as to how the device 
disintegrates or what controls its exit from the stomach. 
Theeuwes and Urquhart, U.S. Pat. No. 4,434,153 describe the use of a device 
(containing a hydrogel) which can enter into the gastrointestinal 
environment where it imbibes fluid and swells 2-50 fold so that it is 
retained in the stomach over an extended period. Small pills containing 
drug are released from this device and subsequently delivered for gastric 
or intestinal absorption. 
The patents of this category teach the use of size to retain the device in 
the stomach and function by absorption of gastric fluid to cause swelling 
of an expandable polymeric material. No indication of the obtainable 
duration is given or of control of the process by which the device 
disintegrates or otherwise is expelled from the stomach. 
(3) Alza Corporation, U.S. Pat. Nos. 3,797,492 and 3,901,232 disclose the 
use of inflatable bags containing a gas or vapor-generating system to 
cause inflation following release of the device from a bioerodible capsule 
in the stomach (or other desired body cavity). The inflated envelope 
causes the device to be retained in the desired site (e.g. stomach) and 
drug is released from an attached delivery system. When all the drug has 
been expelled the envelope deflates and the device passes from the 
stomach. 
These patents imply the use of size to retain the device in the stomach and 
achieve enlarged size in the stomach via conversion of liquid (or solid) 
components to a gaseous form. They do not teach the use of mechanical 
movement to create large forms of the device from a smaller configuration. 
(4) R. Laby, U.S. Pat. No. 3,844,285 describes the use of a device having 
one initial configuration or adapted to be arranged in the configuration 
so as to pass into the rumen of an animal, whereupon, it changes to a 
second configuration which will prevent or hinder regurgitation of the 
device. This patent is applicable to devices which are delivered to the 
rumen and required to remain in the rumen by preventing regurgitation. The 
reference does not teach devices designed to enter and be retained in the 
stomach of humans or other non-ruminant animals. Neither does it teach any 
procedure for preventing passage of such devices through the pylorus of 
humans or non-ruminant animals since only regurgitation is hindered or 
prevented by the device of the reference. The anatomy of the rumen is 
quite different from that of the stomach of non-ruminant species. 
BACKGROUND OF THE INVENTION 
The invention provides a drug delivery device comprising at least one drug 
and a planar disc-shaped or planar multi-lobed figure that is retained in 
the stomach for predictable and extended periods of time for releasing 
therapeutic or other beneficial agents. 
Many orally administered drugs fail to achieve their full potential because 
of a number of problems including: 
a. Slow and incomplete intestinal absorption. 
b. Existence of preferential absorption sites in the gastrointestinal tract 
(absorption windows). 
c. Short biological half-life (in particular if the therapeutic index is 
low). 
Solutions to the delivery problems for these agents cannot be guaranteed 
using conventional controlled release technology since the site of drug 
release may be beyond the site of optimal absorption or the transit time 
through the absorbing portion of the gastrointestinal tract may be too 
short to effect an increase in the duration of action of the drug. In 
order to optimize the delivery of these agents to achieve maximum 
effectiveness (and reduce concentration-related side effects) it is 
desirable to obtain a drug delivery device which would be retained in the 
stomach for a prolonged, predictable period of time during which it would 
release the agent in a predetermined pattern. At the end of its period of 
usefulness, the device would disintegrate or otherwise alter its 
properties such that it would exit from the stomach and pass down the 
intestine. 
Accordingly, it is an object of the invention to provide a means of 
retaining the dosage form in the stomach for an extended, predictable 
period of time. Thereby the duration of absorption and hence the duration 
of action of drugs with short biological half-lives could be extended. 
Likewise the bioavailability of the agents could be improved over that 
achieved from a conventional dosage form or conventional sustained release 
preparation. 
Another object of the invention is to provide a mechanism whereby after a 
predetermined time the device will erode, disintegrate or otherwise alter 
its properties and pass out of the stomach and into the intestine. In 
addition the device should not lodge in the intestine thereby causing an 
obstruction. 
A further object is to devise a device which will not obstruct the passage 
of food while the device is in the stomach or after it has passed into the 
intestine. 
Other objects, features and advantages of the invention will be apparent to 
one skilled in the art from the detailed description of the invention 
which follows.

DESCRIPTION OF THE INVENTION 
The invention is directed to a gastric retention device comprising a planar 
disc-shaped or planar multi-lobed figure prepared from at least one 
erodible polymer, said device having the following properties: 
(a) compressible to a size suitable for swallowing; 
(b) expandable to a size which will prevent passage through the pylorus for 
a predetermined time; 
(c) sufficiently resistant to forces by a stomach to prevent passage 
through a pylorus for a predetermined time; and 
(d) erodible in the presence of gastric juices so that said device after a 
predetermined time is no longer able to retain or attain the expanded 
configuration defined in (b) above and/or resist the forces as defined in 
(c) above. 
The invention is also directed to a method for the controlled release over 
a period of time of a drug in the stomach, comprising a planar disc-shaped 
or planar multi-lobed figure prepared from at least one erodible polymer, 
said device having the following properties: 
(a) compressible to a size suitable for swallowing; 
(b) expandable to a size which will prevent passage through a pylorus for a 
predetermined time; 
(c) sufficiently resistable to forces by a stomach to prevent passage 
through a pylorus for a predetermined time; and 
(d) erodible in the presence of gastric juices so that said device after a 
predetermined time is no longer able to retain or attain the expanded 
configuration defined in (b) above and/or resist the forces as defined in 
(c) above. 
Definitions 
Gastric retention device is a device which resides in the confines of the 
stomach for the purpose of providing a platform for controlled release of 
biologically active agents. 
A planar disc-shaped or multi-lobed flat or planar device may be used which 
is large enough and rigid enough such that said device will not pass out 
of the stomach but will allow passage of food around said device. 
Preferred configurations are illustrated in FIGS. 1-6. 
The longest diameter (the device need not be symmetrical) of the device may 
vary between 1.6 and 5 cm; more preferably in the range 2.0 to 4 cm; and 
most preferably in the range 3.2 to 3.6 cm. 
The expanded devices shown in FIGS. 1, 3 and 5 are compressed by folding or 
rolling to subsequently obtain the form of FIGS. 2a, 4a, and 6a 
respectively and ultimately inserted into capsules as illustrated in FIGS. 
2b, 4b and 6b. 
Criterion A means that the desired expanded configuration of said device is 
too large to be swallowed and thus must be compressed and contained in a 
conventional capsule or like container for swallowing. The capsule is 
designed to dissolve after oral ingestion within the confines of the 
stomach. 
Criterion B means that after the compressed device within the capsule 
container reaches the stomach, upon dissolution and/or disintegration of 
the retaining capsule or like container, said device will expand or unfold 
in such a manner that results in its original shape which is too large to 
pass from the stomach into the intestine unless enough force is applied to 
recompress the device. This "expanded" form of the device will remain in 
the stomach for a pre-determined period of time depending on the desired 
time profile of release of the biologically active agent, which is a part 
of the device or contained within a controlled release module that is 
attached to the retention device. The "pre-determined time" is preferably 
within the range of 1 hour to 1 year. For example, a biologically active 
agent which prevents heart-worm infestation in dogs might require gastric 
retention and controlled delivery of said agent over the course of 6-12 
months. This period depends on the seasonal changes of the mosquito 
population which is the main vector of heart worm infection in dogs. A 
second example is the use of such a gastric retention device to maintain 
controlled delivery of a contraceptive agent. The desired retention time 
of the device might be 3-4 weeks to coincide with the normal frequency of 
menses. A third example is the use of such a device to achieve once daily 
dosing, if such device is coupled to a controlled release device for 
delivery of an agent with a very short half-life of biological activity, 
such as a dopamine agonist for treatment of Parkinsonism. 
Criterion C means that the device in question must sustain some compressive 
force, in excess of that amount the stomach is able to apply, in order for 
said device to not prematurely pass on into the intestine. For humans and 
animals with similar gastric anatomy such as dogs, the gastric pouch is 
capable of applying forces of 50-150 grams. 
Criterion D means that after some predetermined time, during which said 
device has been utilized, some part of the device will suddenly or 
gradually fail to meet Criteria B and/or C. That is, the device will 
either be unable to withstand a lesser compressive force, or will lose its 
integrity as a single unit, and thereby be subject to the normal 
propulsive forces and pass out of the stomach. By doing so, the danger of 
multiple devices causing obstructive problems, is obviated. 
These devices can be manufactured by a number of processes including 
injection molding, extrusion, film-forming, laminating and the like as 
will be clear to one skilled in the art. For example, a mold cn be 
constructed in the desired shape of the device and filled with appropriate 
material(s) in the liquid state and then allowed to cure by chemical 
processes or cooling if thermosetting material(s) is used. 
A critical property of the devices is that, after a certain, pre-determined 
period of time in the stomach they will alter their properties in a manner 
which will permit their elimination from the stomach into the intestine. 
For this purpose the devices must contain component(s), sections(s) or 
points(s) which will erode or dissolve in the aqueous environment of the 
stomach. 
For example, the four lobes of the device of FIG. 1 may be fastened at a 
central point by glue (or other material) which will dissolve or erode 
during the desired time period, thereby liberating the individual lobes 
which will then easily pass out of the stomach. 
The disc can be manufactured from composite materials such that one or more 
component(s) will erode or dissolve leaving a disc whose mechanical 
properties are such that it can be readily removed from the stomach by the 
compression forces associated with the recurrent interdigestive migratory 
myoelectric complex. 
A further modification of the four-lobed form is to have contained within 
the lobes an erodible or dissolving structure which will maintain the 
lobes in a rigid configuration until the internal, structurally supporting 
material has disintegrated. At that point the device would be incapable of 
maintaining its rigid, planar conformation and would be eliminated from 
the stomach. (see FIG. 3 and Example 2) 
Likewise these devices can be manufactured from materials which are 
entirely erodible. 
Representative erodible polymers which can be employed in the practice of 
the invention are cellulosics such as Klucel (hydroxypropylcellulose), 
cellulose acetate phthalate, methyl cellulose, 
hydroxypropylmethyl-cellulose phthalate and the like; ethylene/vinyl 
alcohol copolymer; ethylenemaleic anhydride copolymer; polyacrylates such 
as Eudragit E (cationic copolymer based on dimethylaminoethyl 
methylacrylate and neutral methylacrylic acid esters), poly(acrylic acid), 
poly(methacrylic acid) and the like; polylactones such as 
poly(caprolactone) and the like; polyanhydrides such as 
poly[bis-(p-carboxyphenoxy)propane anhydride], poly(terephthalic acid 
anhydride) and the like; polyvinyl pyrrolidone; polyamides and 
polypeptides such as polylysine, polyglutamic acid and the like; gelatin 
and derivatives such as those produced on reaction with 
N-acetyl-homo-cysteine thiolactone and the like; polyesters such as 
polylactides, polyglycolides, poly(betahydroxybutyric acid) and the like; 
poly(ortho esters) such as copolymers of DETOSU with diols such as hexane 
diol, decane diol, cyclohexane dimethanol, ethylene glycol, polyethylene 
glycol and incorporated herein by reference those poly(ortho) esters 
described and disclosed in U.S. Pat. No. 4,304,767 and the like; 
polyurethanes such as those prepared with poly(tetramethylene oxide), 
prepolymer terminated with hexamethylene diisocyanate and a poly 
functional diester of oxalic acid and glycerol, 
di-(2,3-dihydroxypropyl)oxalate or its mixture with 
3,6-dioxaoctane-1,8-diol and the like; polyacrylonitriles such as 
poly(alkyl-.alpha.-cyanoacrylates) wherein the alkyl is methyl, ethyl, 
propyl, butyl, amyl and the like; and types of inorganic glass based on 
polyphosphates and fused salts. 
Representative non-erodible polymers that may be employed in the practice 
of the invention are polyolefins such as polyethylene, polypropylene, 
ethylene vinyl acetate copolymers, poly(tetrafluoroethylene) and the like; 
rubbers such as silicon based rubber, styrene-butadiene copolymers and the 
like polyamides such as nylon 6,6, nylon 6, and the like; polyesters such 
as poly(ethylene terephthalate) and the like; polyurethanes formed from 
diisocyanates such as 1,6-hexane diisocyanate or biphenylene diisocyanate 
etc. and diols such as ethylene glycol, 1,4-butane diol and the like; and 
cellulosics such as ethyl cellulose, cellulose diacetate, cellulose 
triacetate and the like. 
A drug or medicament may be associated with the gastric retention device in 
different ways, depending on the physical and chemical properties of the 
drug or medicament. For example, the drug may be dispersed as a solution 
or suspension within an erodible polymer matrix such that as the matrix 
erodes within the confines of the gastric pouch, the drug is released at a 
predetermined rate. Similarly, the drug may be dissolved or dispersed 
within a non-erodible matrix material comprising part of the retention 
device. As this matrix comes in contact with gastric fluid, the drug 
diffuses out of the non-erodible matrix at a predetermined rate. An 
alternative to incorporating the drug as an integral part of the gastric 
retention device is to simply fasten a controlled release drug module to 
the retention device. Such a module might be a miniature constant-flow 
pump, either mechanically or osmotically driven, and may be fastened to 
the retention device by gluing or tethering. Likewise it may consist of a 
matrix system, erodible or non-erodible, fastened to the retention device. 
In man and similarly-sized non-ruminate mammals, the size of the pyloric 
valve between the stomach and small intestine is generally in the range of 
3-5 cm maximum inner circumference. Objects with a mimimum circumference 
of more than 5 cm will generally not pass from the stomach through the 
pylorus. The devices described herein are designed to present a minimum 
circumference of more than 5 cm after deployment in the stomach. Before 
deployment in the stomach the minimum circumference is less than 2 cm. 
The active agents (therapeutic agent or other beneficial agents) which can 
be utilized in accordance with the practice of the invention is not 
critical. Any agent which can be obtained in a stable form is applicable 
herein. As to the amount of active agent which can be delivered in 
accordance with the invention, said amount depends on a variety of factors 
such as the host, physical attributes, particular disease or disorder 
being treated and of course the severity of the condition being treated. 
The amount of active agent utilizable in the invention is known to one 
skilled in the art and is disclosed in various medical references such as 
PDR and etc. or could be obtained from suitably designed clinical trials. 
Generally, the amount of polymer employed in the practice of the invention 
ranges from 10% to 99.9% polymer (preferably 20% to 60%) by weight of the 
drug delivery platform. The remaining portion of the composition contains 
the medicament and conventional pharmaceutically acceptable excipients. 
Representative pharmaceutically acceptable excipients that the drug 
delivery device may contain are buffering agents and preservatives. 
Suitable water soluble preservatives which may be employed in the drug 
delivery device are sodium bisulfite, sodium thiosulfate, ascorbate, 
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric borate, 
parabens, benzyl alcohol and phenylethanol. These agents may be present in 
amounts from 0 to 5% by weight. Suitable water soluble buffering agents 
are alkali or alkali earth carbonates, phosphates, bicarbonates, citrates, 
borates, acetates, acid anhydrides, succinates and the like, such as 
sodium phosphate, citrate, borate, acetate, bicarbonate and carbonate. 
These agents may be present in amounts sufficient to maintain some optimum 
pH of the system in the range 1 to 9. As such the buffering agent can be 
as much as 25% on a weight to weight basis of the total composition. 
The following examples illustrate the preparation of various drug delivery 
devices of the invention. The Examples should be construed as 
illustrations rather than limitations thereof. 
EXAMPLE 1 
Studies were performed with Beagle dogs in order to ascertain gastric 
retention time of the drug delivery device described herein. The 
parameters investigated were size, shape and erodibility. These devices 
were administered in gelatin capsules and their position in the 
gastrointestinal tract determined using x-ray techniques. 
The results for disc and 4-lobed planar devices of different dimensions and 
made from Silastic (Dow Company) medical grade silicone rubber labelled 
with 15% barium sulfate are shown below. 
______________________________________ 
% Retained 
Shape Dimensions at 24 hrs. 
N* 
______________________________________ 
Disc 2.5 cm diameter 
67 9 
4-lobed figure 
3.2 cm diameter 
90 10 
2.7 cm diameter 
83 12 
2.2 cm diameter 
60 10 
______________________________________ 
*Number of trials 
These data indicate that the retention of these devices in the stomach is a 
function of their diameter and that retention for a period of 24 hours is 
possible using devices which can be folded into gelatin capsules suitable 
for swallowing. 
EXAMPLE 2 
The effect of erosion on the performance of one of the devices is 
demonstrated in this example. The planar cross form shown in FIG. 5 was 
constructed containing segments of rigid, bioacceptable material. For this 
example segments of spaghetti were inserted into hollows in the limbs of 
the cross. When the device came into contact with water, the spaghetti 
segments absorbed water and lost their rigidity. The overall effect was to 
produce a device which had lost its integrity and which could be more 
readily expelled from the stomach by the forces of the interdigestive 
migratory myoelectric complex. The data from one such experiment using 
Beagle dogs are shown below. 
______________________________________ 
% Retained in 
Shape stomach at 24 hrs. 
N 
______________________________________ 
cross with non- 100% 2 
eroding limbs 
cross with eroding 
71% 7 
limbs (spaghetti) 
cross with empty 
57% 7 
limbs 
______________________________________ 
The data show that the cross-form with hollow limbs is much less-well 
retained than the same shape with rigid, non-eroding limbs. The device 
with initially rigid, but eroding, limbs was intermediate in performance.