Oral osmotic device with hydrogel driving member

An osmotic device for delivering a beneficial drug, such as an anti-fungal, into the mouth of a human patient is disclosed. The device has a size and shape adapting it to be comfortably retained in the mouth for extended periods of time. The device comprises a wall surrounding a compartment housing a layer of an agent that is insoluble to very soluble in aqueous biological fluid, e.g., saliva, and a layer of a fluid swellable, hydrophilic polymer. A passageway in the wall connects the agent with the exterior of the device. The wall is permeable to the passage of aqueous biological fluid but substantially impermeable to the passage of the hydrophilic polymer. In one embodiment the beneficial agent has a different color than the hydrophilic polymer. The wall is sufficiently translucent to permit the patient to see the amount of drug/beneficial agent remaining to be delivered. Marking lines may be provided on the wall indicating the amount of drug/agent which has been delivered and/or the amount remaining to be delivered.

TECHNICAL FIELD 
This invention pertains to an osmotic device for delivering a beneficial 
agent into the oral cavity of a patient. More particularly, the invention 
relates to an osmotic device comprising a shaped semipermeable wall 
surrounding a compartment containing a beneficial agent that is insoluble 
to very soluble in an aqueous fluid, and a layer of a water-swellable 
hydrophilic polymer driving member. A passageway through the wall connects 
the exterior of the device with an agent for delivering the agent from the 
device into the oral cavity. Means are provided for displaying the amount 
of agent remaining to be delivered. 
BACKGROUND ART 
Osmotic devices for delivering beneficial agents to environments of use are 
known to the prior art in U.S. Pat. Nos. 3,845,770 and 3,916,899 issued to 
Theeuwes et al. The osmotic devices disclosed in those patents comprise a 
semipermeable wall that surrounds a compartment containing an agent. The 
wall is permeable to the passage of an external fluid, and substantially 
impermeable to the passage of agent. There is a passageway through the 
wall for delivering the agent from the device. These devices release agent 
by fluid being imbibed through the wall into the compartment at a rate 
determined by the permeability of the wall and the osmotic pressure 
gradient across the wall to produce an aqueous solution containing agent 
that is dispensed through the passageway from the device. These devices 
are extraordinarily effective for delivering an agent that is soluble in 
the fluid and exhibits an osmotic pressure gradient across the wall 
against the fluid, and for delivering an agent that has limited solubility 
in the fluid and is admixed with an osmotically effective compound that is 
soluble in the fluid and exhibits an osmotic pressure gradient across the 
wall against the fluid. Devices of this type are typically designed to be 
swallowed or implanted to deliver a drug or other beneficial agent to the 
body. 
In U.S. Pat. No. 4,111,202, the delivery kinetics of the device are 
enhanced by manufacturing the device with an agent compartment and an 
osmagent compartment separated by a film, which film is movable from a 
rested to an expanded state. The device delivers agent by fluid being 
imbibed through the wall into the osmagent compartment producing a 
solution that causes the compartment to increase in volume and act as a 
driving force that is applied against the film. This force urges the film 
to expand against the agent compartment and correspondingly diminish the 
volume of this compartment, whereby agent is dispensed through the 
passageway from the device. While this device operates successfully for 
its intended use, and while it can deliver numerous difficult to deliver 
agents, its use is somewhat limited because of the manufacturing steps 
needed for fabricating and placing the movable film in the device. 
In U.S. Pat. No. 4,327,725 Cortese et al provided an osmotic dispensing 
device for delivering a beneficial agent which, because of its solubility 
in an aqueous biological fluid is difficult to deliver in meaningful 
amounts at controlled rates over time. The osmotic device of this patent 
comprises a semipermeable wall surrounding a compartment containing a 
beneficial agent that is insoluble to very soluble in an aqueous 
biological fluid and an expandable hydrogel. In operation, the hydrogel 
expands in the presence of external fluid that is imbibed into the device 
and in some operations mixes with the beneficial agents, thereby forming a 
dispensable formulation that is dispensed through the passageway from the 
device. This device operates successfully for its intended use, and it 
delivers many difficult to deliver beneficial agents for their intended 
purpose. 
When administering a drug buccally (i.e., by absorption of the drug through 
the highly vascularized buccal tissues of the mouth) a number of 
conditions are present which makes it difficult to effectively deliver 
drug in a therapeutically effective amount for a prolonged period of time 
(e.g., for periods greater than several minutes). For example, when a 
patient is given a drug-containing lozenge, there is a natural tendency to 
suck and chew on the lozenge thereby effectively reducing the time period 
during which the drug can be buccally administered by the lozenge. In 
addition, the action of saliva and swallowing by the patient effectively 
reduces the concentration of drug along the buccal membranes of the oral 
cavity and further causes much of the drug to be swallowed, in many cases 
rendering it inactive upon encountering the low pH environment of the 
stomach. This has been a particular problem in treating diseases of the 
mouth which require constant local administration of drug. One such 
disease condition is candidiasis of the oral cavity. A recent study has 
shown that 94% of male patients having acquired immunodeficiency syndrome 
(AIDS) and 72% of those with AIDS-related complex (ARC) had oral 
candidiasis (Barr & Marder, AIDS: A Guide For Dental Practice, pp. 53-62, 
1987). Recommended treatment of oral candidiasis is by continuous dosing 
of selected anti-fungal agents in the mouth, pharynx and oesophagus. 
Typically, therapeutically recommended doses of nystatin, amphotericin B 
or miconazole, either in the form of liquid rinses or slowly dissolving 
pastilles and tablets have been used to treat oral candidiasis. 
Unfortunately, when the anti-fungal agents are administered by gargling or 
with rinses, the anti-fungal agents are cleared from the mouth in a matter 
of minutes. While the duration of drug delivery is increased somewhat 
using slowly dissolving pastilles and tablets, typically these release 
drug for no more than about 15 to 20 minutes. Accordingly, these dosage 
forms require frequent repetitive dosing (e.g., gargling every five 
minutes or taking a lozenge 3-4 times per hour) in order to effectively 
treat the condition. 
Thus, there has been a clear need in the art of treating oral diseases, 
such as oral candidiasis, for a dosage form which is able to continuously 
deliver therapeutically effective amounts of drug or other beneficial 
agent into the oral cavity for extended periods of time, i.e. periods 
greater than about 15 to 20 minutes. 
In response to the problem of short duration of drug delivery from rinses, 
pastilles and tablets, the use of an elementary osmotic pump to deliver 
medication to the buccal tissues has been suggested. Elementary osmotic 
pumps are typically formed by compressing a tablet of an osmotically 
active drug (or an osmotically inactive drug in combination with an 
osmotically active agent or osmagent) and then coating the tablet with a 
semipermable membrane which is permeable to an exterior aqueous-based 
fluid but impermeable to the passage of drug and/or osmagent. One or more 
delivery orifices may be drilled through the semipermeable membrane wall. 
Alternatively, orifice(s) through the wall may be formed in situ by 
incorporating leachable pore forming materials in the wall. In operation, 
the exterior aqueous based fluid is imbibed through the semipermeable 
membrane wall and contacts the drug and/or salt to form a solution or 
suspension of the drug. The drug solution or suspension is then pumped out 
through the orifice as fresh fluid is imbibed through the semipermeable 
membrane. 
While the use of elementary osmotic pumps has proven to be very successful 
in delivering drugs through the gastro-intestinal (GI) tract (i.e., by 
swallowing the elementary osmotic pump), there are several problems with 
buccal administration. As with drug-containing lozenges, there is a 
natural tendency for the patient to suck and chew on the drug-containing 
elementary osmotic pumps. Chewing in particular tends to compress the 
deformable membrane wall, thereby squeezing the drug solution or 
suspension out of the device at an accelerated rate. The duration of drug 
delivery is therefore severely curtailed. For example, when an elementary 
osmotic pump, designed to deliver drug at a relatively constant rate over 
a period of 12 to 24 hours within the GI tract, is placed in the oral 
cavity and subjected to patient sucking and chewing, the device delivers 
the entire drug dose relatively quickly, sometimes in less than about an 
hour. 
Thus, there has been a need in the art of treating oral diseases for a 
dosage form which is osmotically driven but which is able to continuously 
deliver a drug within the mouth to the buccal membranes and which is 
relatively unaffected by the patient sucking and chewing on the device. 
Another proposed solution to the problem of short duration of drug delivery 
from rinses, pastilles, and tablets, has been a delivery device comprised 
of a hydrophilic polymer having a drug dispersed therein. When placed 
between the cheek and gum of a patient, the hydrophilic polymer absorbs 
moisture from the buccal membrane, eventually adhering itself to the 
membrane surface. While it is desirable from the standpoint of patient 
comfort and convenience to adhere the delivery platform directly to the 
buccal membrane, this can create a problem when delivering a drug having a 
tendency to cause irritation. When delivering an irritating drug, these 
devices tend to magnify the irritation since the device is adhered to the 
buccal membrane and maintains a high concentration of the irritating drug 
at a single membrane site. 
Thus, there has been a need in the art of treating oral diseases for a 
dosage form which is able to continuously deliver a potentially irritating 
drug for extended periods of time without causing irritation. 
Of course, with any dosage form designed to deliver a drug into the oral 
cavity for an extended period of time, means must be provided for alerting 
the patient when a predetermined dose of the drug has been delivered. For 
example, in cases where the recommended treatment is continuous delivery 
of drug into the mouth of the patient, a signaling means for alerting the 
patient when the entire dosage has been delivered is required. In the case 
of a dosage form designed to deliver a predetermined percentage of the 
dose buccally and the remainder of the dose through the GI tract, the 
dosage form must be provided with means for signaling the patient when the 
predetermined perecentage of the dose has been delivered. 
DISCLOSURE OF THE INVENTION 
Accordingly, it is an object of this invention to provide an osmotic device 
for the controlled delivery of a beneficial agent to the oral cavity of an 
animal, and in particular a human, for an extended period of time. 
It is another object of the invention to provide an oral osmotic device 
useful for delivering an agent into the mouth of a patient, which agent is 
difficult to deliver and can be delivered by the subject device at a 
pharmaceutically effective rate and over an extended period of time. 
It is another object of the invention to provide an oral osmotic device 
having a compartment containing an active agent that can be from insoluble 
to very soluble in an aqueous fluid which is present in the oral cavity, 
and an expandable driving member consisting of a layer of a hydrophilic 
polymer, which operates to diminish the volume occupied by the active 
agent, thereby delivering the agent from the device at a controlled rate 
over an extended period of time, the agent being released from the device 
in the form of a solution and/or suspension. 
It is yet another object of the invention to provide an oral osmotic 
therapeutic device that can administer a complete pharmaceutical dosage of 
a very soluble or a poorly soluble agent, at a controlled and continuous 
rate into the mouth of an animal, for an extended delivery period and 
which device signals the animal when the complete dose of beneficial agent 
has been delivered. 
It is a further object of the invention to provide an oral osmotic 
therapeutic device that can administer a complete pharmaceutical dosage of 
a very soluble, or a poorly soluble agent, at a controlled and continuous 
rate into the mouth of a human, for an extended delivery period and which 
device displays the amount of beneficial agent which has been delivered 
and the amount of beneficial agent which still remains in the device to be 
delivered. 
It is a still further object of the invention to provide an oral osmotic 
therapeutic device that can administer a potentially irritating drug into 
the mouth of a human for an extended period of time without causing 
irritation to the buccal membrane. 
Other objects, features, aspects and advantages of the invention will be 
more apparent to those versed in the art from the following detailed 
specification taken in conjunction with the figures and the accompanying 
claims. 
This invention concerns an osmotic device for controlled delivery of an 
active beneficial agent into the oral cavity of an animal, such as a 
human. The device comprises a wall formed of a material which is permeable 
to the passage of an external aqueous fluid which is present in the oral 
cavity (e.g., saliva). The wall material may be either substantially 
impermeable or partially permeable to the passage of the active agent. The 
wall surrounds and forms a compartment that communicates with the exterior 
of the device through one or more passageways in the wall. The compartment 
contains an active agent exhibiting any degree of solubility in the 
aqueous fluid. For example, the agent may be soluble in the exterior fluid 
and exhibit an osmotic pressure gradient across the wall against the 
fluid, or the agent may be completely insoluble in the fluid and be 
admixed with an osmotic agent which exhibits an osmotic pressure gradient 
across the wall against the fluid. In either instance, the agent is next 
to the passageway. The compartment also contains a layer of an expandable 
driving member formed of a water-swellable hydrophilic polymer. The wall 
material is substantially impermeable to the hydrophilic polymer. The 
hydrophilic polymer absorbs fluid imbibed into the compartment, and can 
expand from a rested to an expanded state The hydrophilic polymer is in 
contact with the agent formulation and positioned distant from the 
passageway. Agent is released form the device by the combined actions of 
fluid being imbibed through the wall into the compartment producing a 
solution or suspension containing agent, and by fluid being imbibed by the 
hydrophilic polymer causing it to expand and increase in volume, thereby 
exerting a force against the solution or suspension that decreases their 
respective volume, whereby the agent is released through the passageway at 
a rate controlled by the permeability of the wall, the osmotic pressure 
gradient across the wall, and the rate of expansion of the driving 
hydrophilic polymer over a prolonged delivery period. The device has a 
size and shape allowing it to be comfortably retained in the oral cavity 
for an extended period of time. 
The device is provided with a mechanism for signaling the animal when the 
dose of beneficial agent has been delivered from the device. In one 
embodiment, the mechanism includes providing the layer of the beneficial 
agent with a taste which contrasts with the hydrophilic polymer layer 
taste. In a preferred embodiment, the layer of active agent contains a 
first flavoring agent while the hydrophilic layer contains a second 
flavoring agent having a flavor easily distinguishable from the flavor of 
the first flavoring agent. During use, the active agent is co-delivered 
with the first flavoring agent. The patient can easily recognize that the 
device is delivering drug due to the flavor of the first flavoring agent. 
Eventually, the entire dose of active agent is delivered. At this point, 
the device also stops delivering the first flavoring agent. Thereafter, 
the device begins delivering the hydrophilic polymer and the second 
flavoring agent. Upon tasting the second flavoring agent, the patient 
knows that the device has delivered the entire dose of beneficial agent. 
In another embodiment, the mechanism for signaling the animal also displays 
the amount of beneficial agent present in the device. In a preferred 
embodiment, the active agent and the hydrophilic polymer have contrasting 
colors. The semipermeable wall is made sufficiently translucent to permit 
the patient to see the relative amounts of active agent and hydrophilic 
polymer present in the compartment.

DETAILED DESCRIPTION OF THE INVENTION 
Turning now to the drawings, one example of an oral osmotic device is shown 
in FIGS. 1 through 4, and is indicated by the numeral 10. Device 10 is 
comprised of a wall 12 that surrounds and forms a compartment 13, as seen 
in the sectional views of FIGS. 3 and 4. Compartment 13 comprises a layer 
of a beneficial agent, identified by dots 14, that can be from insoluble 
to very soluble in an exterior aqueous fluid, indicated by dashes 15. When 
agent 14 is soluble in fluid 15, it exhibits an osmotic pressure gradient 
across wall 12 against the exterior fluid 15 imbibed into compartment 13. 
Compartment 13 in another embodiment contains a layer of agent 14 that has 
limited solubility or is substantially insoluble in fluid 15, and it 
exhibits a limited, or it may not exhibit any osmotic pressure gradient 
across wall 12 against the exterior fluid. When agent 14 has a limited 
solubility, or if it is substantially insoluble in fluid 15, it can be 
mixed with an osmagent that is soluble in the external fluid and exhibits 
an osmotic pressure gradient across wall 12 against the fluid. Wall 12 is 
formed of a polymeric material that is substantially permeable to the 
passage of the external fluid, and either impermeable or partially 
permeable to the passage of agent and osmagent. The polymer forming wall 
12 is non-toxic and it maintains its physical and chemical integrity 
during the life of device 10. 
Compartment 13 further houses a layer of an expandable driving member 16 
composed of a hydrophilic polymer, optionally cross-linked, which 
possesses osmotic properties such as the ability to imbibe external fluid 
and exhibit an osmotic pressure gradient across the wall 12 against the 
fluid. Wall 12 is substantially impermeable to the passage of the 
hydrophilic polymer in driving layer 16. Layer 16 absorbs fluid imbibed 
into the compartment and swells. The osmotic pressure of the hydrophilic 
polymer network is the driving force of the swelling, expanding layer 16. 
Layer 16 is in contact with agent 14 and at the interface 18 formed by the 
hydrophilic polymer and the agent, a thin precipitate preferably forms. 
The precipitate is especially preferred when the active agent is soluble 
in the imbibed fluid. The precipitate forms in the presence of a solution 
containing the agent, or the agent and an osmagent, and it is 
substantially impervious and restricts the passage of agent 14 into layer 
16. The precipitate further serves as an in situ formed membrane integral 
with the hydrophilic polymer for applying pressure against agent 14 during 
operation of device 10. When the active agent is substantially insoluble, 
interface 18 can be achieved simply by maintaining a difference in the 
viscosity values of layers 14 and 16. For example, layer 16 can be 
formulated with a hydrophilic polymer having a high molecular weight and a 
high degree of cross-linking. In such a case, there is negligible 
penetration of insoluble agent suspension into layer 16. 
Device 10 releases agent 14 through one or more passageways 17 in wall 12 
that communicates agent 14 with the exterior of device 10. Device 10 
releases agent 14 by fluid being imbibed into compartment 13 in a tendency 
towards osmotic equilibrium at a rate determined by the permeability of 
wall 12 and the osmotic pressure gradient across wall 12. The imbibed 
fluid continuously forms a solution of the agent 14, or in cases where the 
agent 14 has limited or no solubility in the fluid a solution of osmagent 
containing the agent 14 in suspension, which solution in either instance 
is released by the combined operation of device 10. These operations 
include the solution/suspension being osmotically delivered through 
passageways 17 due to the continuous formation of solution/suspension in 
the compartment 13, and by the hydrophilic polymer layer 16 swelling and 
applying pressure against the solution/suspension thereby delivering it to 
the exterior of device 10. 
Compartment 13 operates to substantially insure that delivery of agent 14 
from compartment 13 is constant over a prolonged period of time by two 
methods. First, hydrophilic polymer layer 16 operates to continuously 
concentrate agent 14 by imbibing some fluid from agent 14 to keep the 
concentration of agent 14 from falling below saturation. Secondly, layer 
16 by imbibing external fluid 15 across wall 12 continuously increases its 
volume, as illustrated by the expansion of layer 16 from that shown in 
FIG. 3 to that shown in FIG. 4, thereby exerting a force on agent 14 and 
diminishing the volume of agent 14, thusly concentrating agent 14 in 
compartment 13. The swelling of layer 16, along with the simultaneous, 
corresponding reduction of volume of agent 14, assures the delivery of 
agent 14 at a controlled rate over time. 
Device 10 of FIGS. 1-4 is designed for oral use, that is, for releasing 
either a locally or systemically acting therapeutic agent in the oral 
cavity of an animal, such as a human, over an extended period of time. 
Because the device is designed to be retained in the mouth for periods on 
the order of about 0.5 to 12 hours, the device must have an exterior shape 
which is comfortably retained in the mouth. It has been found that an 
oblong or elliptically shaped device 10 is preferred from a comfort 
standpoint. As shown in FIGS. 1 and 2, device 10 has a length 1, a width 
w, and a height h. It has been found that devices 10 having an aspect 
ratio, which ratio is the ratio of 1:w, of about 1.2:1 to about 3:1 are 
most comfortably retained in the mouths of humans. Preferably, the device 
10 has an aspect ratio of about 1.3:1 to about 2:1, and most preferably 
about 1.5:1 to about 1.7:1. In addition, in order to fit comfortably 
between the cheek and gum of a patient, the device has a height of about 
0.5 to about 10 mm, preferably about 2 to about 8 mm, and most preferably 
about 3 to about 5 mm. The device also has a volume of less than about 2 
cm.sup.3, preferably about 0.1 to about 0.5 cm.sup.3, and most preferably 
about 0.25 cm.sup.3. 
Osmotic delivery device 10 has a mechanism for displaying the amount of 
drug formulation remaining in the device for delivery into the patient. In 
one preferred embodiment, the display means comprises color contrast 
between the drug formulation 14 and the driving layer 16, in combination 
with a translucent wall 12. In this embodiment, the color of the drug 
formulation 14 is chosen to provide good visual contrast with the color of 
the driving layer 16. The color of the drug formulation 14 can be achieved 
using any number of coloring techniques known in the art. For example, the 
drug itself may have a natural color which itself adequately contrasts 
with the natural color of the driving layer 16. On the other hand, a 
number of pharmaceutically acceptable dyes or coloring agents may be mixed 
with either the drug formulation 14 and/or the driving layer 16 in order 
to provide the appropriate color contrast. Suitable pharmaceutically 
acceptable coloring agents, both natural and synthetic, are known in the 
art. See Remington's Pharmaceutical Sciences, 14th Ed., pp 1319-1321. 
In accordance with this embodiment of the invention, the patient can easily 
determine the amount of agent 14 remaining in compartment 13 simply by 
visually inspecting device 10. For example, the drug formulation 14 may 
have a white color and the layer 16 may be dyed to achieve a red color. 
When the device is first placed in the mouth of the patient, the white and 
red layers are clearly visible through the translucent semipermeable wall 
12. After a period of time in the patient's mouth, the device 10 will 
imbibe aqueous fluid (e.g., saliva) thereby causing a solution or 
suspension of the drug 14 to be formed and also causing the hydrogel 16 
layer to expand. Because the drug layer and the hydrophilic polymer layer 
have contrasting colors the patient can easily determine the relative 
amount of drug remaining in the device for delivery. This can have a 
number of useful applications. For example, in treating a condition 
requiring substantially continuous delivery of drug to the oral cavity, 
the patient is alerted when the device 10 has delivered all of the drug. 
At this point, only the red hydrophilic polymer layer remains. This can be 
checked simply by visually inspecting the device. 
In another embodiment, the device of the present invention can be used to 
extend the absorption period of a drug which might be poorly absorbed 
throughout certain portions of the GI tract, such as the colon. In such a 
case, it may be desirable to administer a predetermined percentage of a 
dose of the drug buccally followed by delivery of the remaining dose of 
drug in the device within the GI tract. One example of such a drug is 
captopril, an anti-hypertensive used for the treatment of heart disease. 
Another example is the drug cimetidine, a histamine H.sub.2 receptor 
antagonist used for the treatment of duodenal and gastric ulcers. In such 
cases, the device 10 may be provided with a mark or line 19 on the 
external surface of wall 12 (See FIG. 2). The position of the line 19 
corresponds to the delivery of the predetermined percentage of the dose 
from the device 10. Thus, when the interface 18 between the hydrophilic 
polymer layer 16 and drug 14 layers becomes aligned with the exterior line 
19 on wall 12, the patient is alerted to the fact that the predetermined 
percentage of the dose of drug has been delivered. At this point, the 
patient simply swallows the device and the remaining portion of drug in 
device 10 is administered through the GI tract. 
In another embodiment, a plurality of lines 19 are provided on wall 12. 
Each of the lines 19 is positioned to align with interface 18 after the 
device 10 has been retained in the mouth for a predetermined period of 
time, e.g., a one hour marking line, a two hour marking line, etc. In this 
way, the patient can easily monitor the duration of drug delivery, even 
without access to a clock. 
In another preferred embodiment of the present invention, the mechanism for 
signaling the patient comprises a contrast in taste between the drug 
formulation 14 and the hydrophilic polymer driving layer 16. In this 
embodiment, the flavor of the drug formulation 14 is chosen to provide a 
sharp contrast with the flavor of the hydrophilic polymer driving layer 
16. Preferably, the drug formulation contains a flavoring agent which is 
enjoyed by the patient, while the hydrophilic polymer layer contains a 
flavoring agent having an unpleasant taste. For example, the drug can be 
flavored with peppermint oil while the hydrophilic polymer layer is 
flavored with a salt (e.g., NaCl). The flavor of the drug formulation 14 
can be achieved by any number of flavoring techniques known in the art. 
For example, the drug itself may have a natural flavor which itself 
adequately contrasts with the natural flavor of the hydrophilic polymer 
driving layer 16. On the other hand, a number of pharmaceutically 
acceptable flavoring agents may be mixed with either the drug formulation 
14 and/or the hydrophilic polymer in layer 16 in order to provide the 
appropriate taste contrast. Suitable pharmaceutically acceptable flavoring 
agents, both natural and synthetic, are known in the art. See Remington's 
Pharmaceutical Sciences, 14th Ed., pp 1321-1338. 
Osmotic delivery device 10 can be manufactured with a wall 12 formed of a 
material that does not adversely affect the agent 14 (e.g., a drug), the 
osmagent, if any is present, and the hydrophilic polymer in layer 16. The 
material forming wall 12 should also not adversely affect the buccal 
tissues of the patient. In addition, the material forming wall 12 is 
permeable to the passage of an external aqueous fluid 15, such as water 
and biological fluids naturally present in the oral cavity (e.g., saliva), 
while remaining essentially impermeable to the passage of hydrophilic 
polymer, and optionally impermeable to the passage of agents, including 
drugs, osmagents, and the like. The selectively semipermeable materials 
forming wall 12 are insoluble in fluids naturally present in the oral 
cavity. Typical materials for forming wall 12 include semipermeable 
polymers known to the art as osmosis and reverse osmosis membranes, such 
as cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose 
acetate, cellulose diacetate, cellulose triacetate, agar acetate, amylose 
triacetate, beta glucan acetate, acetaldehyde dimethyl acetate, cellulose 
acetate ethyl carbamate, polyamides, polyurethanes, sulfonated 
polystyrenes, cellulose acetate phthalate, cellulose acetate methyl 
carbamate, cellulose acetate succinate, cellulose acetate 
dimethylaminacetate, cellulose acetate ethyl carbamate, cellulose acetate 
chloracetate, cellulose dipalmatate, cellulose dioctanoate, cellulose 
dicaprylate, cellulose dipentanlate, cellulose acetate valerate, cellulose 
acetate succinate, cellulose propionate succinate, methyl cellulose, 
cellulose acetate p-toluene sulfonate, cellulose acetate butyrate, 
cross-linked selectively semipermeable polymers formed by the 
coprecipitation of a polyanion and a polycation as disclosed in U.S. Pat. 
Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006; and 3,546,142, 
semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat. 
No. 3,133,132, lightly cross-linked polystyrene derivatives, cross-linked 
poly(sodium styrene sulfonate), poly(vinylbenzyltrimethyl ammonium 
chloride), cellulose acetate having a degree of substitution up to 1 and 
an acetyl content up to 21%, cellulose diacetate having a degree of 
substitution of 1 to 2 and an acetyl content of 21 to 35%, cellulose 
triacetate having a degree of substitution of 2 to 3 and an acetyl content 
of 35 to 44.8%, as disclosed in U.S. Pat. No. 4,160,020. Generally, 
semipermeable materials useful for forming wall 12 will have a fluid 
permeability of 10.sup.-5 to 10.sup.-1 (cc.multidot.mil/cm.sup.2 
.multidot.hr.multidot.atm) expressed per atmosphere of hydrostatic or 
osmotic pressure difference across semipermeable wall 12 can be used for 
the intended purpose. 
In accordance with one preferred embodiment of the present invention, at 
least a portion of the material forming wall 12 is sufficiently 
translucent to allow a patient to see the relative amounts of hydrophilic 
polymer 16 and drug 14 remaining in compartment 13. Examples of suitable 
translucent materials include the cellulosic polymers mentioned above. 
Generally, the wall 12 will contain a sufficient amount of translucent 
material to enable the patient to see the drug layer 14 and the 
hydrophilic polymer layer 16 within compartment 13. Suitable amounts of 
translucent materials will depend upon the translucency of the wall 
material, the methods and conditions under which the wall materials are 
formed, as well as the amount of contrast in the colors of the drug and 
hydrogel layers. Suitable amounts of translucent materials can be easily 
determined through routine experimentation using the examples herein. 
The expression "active agent", as used herein includes any beneficial agent 
or compound, that can be delivered from the device into the oral cavity to 
produce a beneficial and useful result. The agent can be insoluble to very 
soluble in the exterior fluid. For example, the agent can be very soluble 
in fluid 15 that enters compartment 13 and function as its own osmotically 
effective solute, or it can be poorly soluble in the fluid and be mixed 
with an osmotically effective compound that is soluble in the fluid for 
delivering an agent from the device. 
In the specification and the accompanying claims, the term "agent" includes 
drug, and the term "drug" includes any physiologically or 
pharmacologically active substance that produces a local or systemic 
effect when administered to the oral cavity of a human. The term 
"physiologically" as used herein denotes the administration of a drug to 
produce normal levels and functions. The term "pharmacologically" denotes 
variations in response to amount of drug administered to the host. 
Stedman's Medical Dictionary, 1966, published by Williams and Wilkins, 
Baltimore, Md. The active drug that can be delivered includes inorganic 
and organic drugs without limitations, those drugs that act on the central 
nervous system, depressants, hypnotics, sedatives, psychic energizers, 
tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, 
analgesics, anti-inflammatory, local anesthetics, muscle contractants, 
antimicrobials, anti-fungals, anti-malarials, hormonal agents, 
contraceptives, sympathomimetics, diuretics, anti-parasitics, neoplastics, 
hypoglycemics, ophthalmics, electrolytes, diagnostic agents, and 
cardiovascular drugs. 
Exemplary drugs that are very soluble in water and can be delivered by the 
devices of this invention include nystatin, chlorhexidine, clonidine, 
sodium fluoride, prochlorperazine adisylate, ferrous sulfate, aminocaproic 
acid, potassium chloride, mecamylamine hydrochloride, procainamide 
hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, 
isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazine 
hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine 
hydrochloride, atropine sulfate, methascopolamine bromide, isopropamide 
iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate 
hydrochloride, oxprenolol hydrochloride, metoprolol tartrate, cimetidine 
hydrochloride, and the like. 
Exemplary drugs that are poorly soluble in water and that can be delivered 
by the devices of this invention include nicotine base, retin A, 
ibuprofen, diphenidol, meclizine hydrochloride, prochlorperazimine 
maleate, phenoxybenzamine, thiethylperazine maleate, anisindone, 
diphenadione erythrityl tetranitrate, dizoxin, isofuraphate, reserpine, 
acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, 
tolzamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum 
aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, progestins, 
esterogenic progestational hormones, corticosteroids, hydrocortisone, 
hydrocorticosterone acetate, cortisone acetate, triamcinolone, 
testosterone, testosterone esters, methyltesterone, 17.beta.-estradiol, 
ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 
17.beta.-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, 
norethindone, norethiderone, progesterone, norgesterone, norethynodrel, 
and the like. 
Examples of other drugs that can be delivered by the osmotic device include 
aspirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac, 
ibuprofen, indoprofen, nitroglycerin, propranolol, metoprolol, valproate, 
oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, 
imipramine, levodopa, chlorpromazine, reserpine, methyl-dopa, 
dihydroxyphenylalanine, pivaloyloxyethyl ester of .alpha.-methyldopa 
hydrochloride, theophylline, calcium gluconate, ferrous lactate, 
vincamine, diazepam, phenoxybenzamine, .alpha.-blocking agents, 
polypeptides, proteins, insulin and the like. The beneficial drugs are 
known to the art in Pharmaceutical Sciences, by Remington 14th Ed., 1979, 
published by Mack Publishing Co., Easton, Pa.; The Drug, The Nurse, The 
Patient, Including Current Drug Handbook, 1974-1976, by Falconer, et al., 
published by Saunder Company, Philadelphia, Pa.; and Medicinal Chemistry, 
3rd Ed., Vol. 1 and 2, by Burger, published by Wiley-Interscience, New 
York. 
The drug can be in various forms, such as uncharged molecules, molecular 
complexes, pharmacologically acceptable salts such as hydrochlorides, 
hydrobromides, sulfate, laurylate, palmitate, phosphate, nitrite, borate, 
acetate, maleate, tartrate, oleate, and salicylate. For acid drugs, salts 
of metals, amines or organic cations, for example quaternary ammonium can 
be used. Derivatives of drugs such as esters, ethers and amides can be 
used. Also, a drug that is water insoluble can be used in a form that is a 
water soluble derivative thereof to serve as a solute, and on its release 
from the device, is converted by enzymes, hydrolyzed by body pH or other 
metabolic processes to the original biologically active form. Drugs in the 
form of polypeptides and proteins, which are susceptible to being broken 
down in the GI tract, can also be delivered systemically by the device of 
the present invention by absorption through the buccal membranes of the 
oral cavity. 
In order to withstand the conditions of use within the oral cavity (i.e., 
patient sucking and chewing of the delivery device), the drug layer 14 
should contain a gelling or suspending agent which prevents the exterior 
wall from collapsing during use. Representative gelling or suspending 
agents include acacia, agaragar, calcium carrageenan, alginic acid, algin, 
agarose powder, collagen, colloidal magnesium silicate, colloidal silicon 
dioxide, sodium carboxy methyl cellulose, partially cross-linked 
polyacrylic acid, polyvinyl pyrrolidone, hydroxyethyl cellulose, 
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene 
oxide, pectin, gelatin, calcium silicate and mixtures thereof. 
Generally, the drug layer 14 typically contains from about 0.5 to about 
99.9 wt % of a gelling or suspending agent, depending on the loading of 
drug/beneficial agent in layer 14 and its solubility in the fluid entering 
the device. Most preferably, the gelling or suspending agent is 
polyethylene oxide, hydroxy propyl methyl cellulose or mixtures thereof. 
The agent including drug, can also be present in the compartment with a 
binder, dispersant, wetting agent and lubricant. Representative of these 
include binders like polyvinyl pyrrolidone, and hydroxypropyl methyl 
cellulose, wetting agents such as fatty amines and fatty quaternary 
ammonium salts, and lubricants such as magnesium stearate and stearic 
acid. The phrase drug formulation indicates the drug is present in the 
compartment accompanied by a gelling or suspending agent, an osmagent, a 
binder, dye or the like. 
The amount of agent initially present in the device is not critical, 
however it is preferred to initially provide an amount of active agent, 
which agent is soluble in fluid entering the device, in excess of the 
amount that can be dissolved in the fluid that enters the device. Under 
this physical state, when the agent is in excess, the device will 
osmotically operate to give a substantially constant rate of release. 
Generally, the device can house from about 0.05 ng to 500 mg or more of 
drug, carrier, fillers, excipients, etc. with individual devices 
containing for example, 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, and the 
like. 
The osmagent present in the device, when used according to the mode of the 
invention where the beneficial agent is not itself osmotically active, are 
osmotically effective compounds soluble in the fluid that enters the 
device, and exhibits an osmotic pressure gradient across the semipermeable 
wall against the exterior fluid. Osmotically effective osmagents useful 
for the present purpose include magnesium sulfate, magnesium chloride, 
sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, 
sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, 
d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glycose, 
hydrophilic polymers such as cellulose polymers, mixtures thereof, and the 
like. The osmagent is usually present in an excess amount, and it can be 
in any physical form, such as particle, powder, granule, and the like. The 
osmotic pressure in atmospheres of the osmagents suitable for the 
invention will be greater than zero and generally up to about 500 atm, or 
higher. 
The hydrophilic polymer layer 16 suitable for the purpose of the invention 
are swellable, hydrophilic polymers which interact with water and aqueous 
biological fluids and swell or expand to an equilibrium state. The 
polymers exhibit the ability to swell in water and retain a significant 
portion of the imbibed water within the polymer structure. The polymers 
swell or expand to a very high degree, usually exhibiting a 2 to 50 fold 
volume increase. The polymers can be noncross-linked or cross-linked. The 
swellable, hydrophilic polymers are in one presently preferred embodiment 
lightly cross-linked, such cross-links being formed by covalent ionic 
bonds or hydrogen bonds. The polymers can be of plant, animal or synthetic 
origin. Hydrophilic polymers suitable for the present purpose include 
poly(hydroxy alkyl methacrylate) having a molucular weight of from 30,000 
to 5,000,000; poly(vinylpyrrolidone) having moleuclar weight of from 
10,000 to 360,000; anionic and cationic hydrogels; polyelectrolyte 
complexes; poly(vinyl alcohol) having a low acetate residual, cross-linked 
with glyoxal, formaldehyde, or glutaraldehyde and having a degree of 
polymerization from 200 to 30,000; a mixture of methyl cellulose; 
cross-linked agar and carboxymethyl cellulose; a water insoluble, water 
swellable copolymer produced by forming a dispersion of finely divided 
copolymer of maleic anhydride with styrene, ethylene, propylene, butylene 
or isobutylene cross-linked with from 0.001 to about 0.5 moles of 
saturated cross-linking agent per mole of maleic anhydride in copolymer; 
water swellable polymers of N-vinyl lactams, and the like. 
Other polymers include polymers that form hydrogels such as Carbopol.RTM. 
acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000; 
Cyanamer.RTM. polyacrylamides; cross-linked water sweallable indene-maleic 
anhydride polymers, Goodrite.RTM. polyacrylic acid having a molecular 
weight of 80,000 to 200,000; Polyox.RTM. polyethylene oxide polymers 
having molecular weight of 100,000 to 5,000,000 and higher; starch graft 
copolymers; Aqua-Keeps.RTM. acrylate polymer polysaccharides composed of 
condensed glucose units such as diester cross-linked polyglucan, and the 
like. Representative polymers that form hydrogels are known to the prior 
art in U.S. Pat. Nos. 3,865,108 issued to Hartop; 4,002,173 issued to 
Manning; 4,207,893 issued to Michaels; and in Handbook of Common Polymers, 
by Scott and Roff, published by the Chemical Rubber Company, Cleveland, 
Ohio. 
For the purpose of the invention, the phrase agents with degrees of 
solubility as used herein indicates, agents that are insoluble to very 
soluble in aqueous biological fluids present in the oral cavity, such as 
saliva. Further for this purpose, an insoluble agent indicates a 
solubility of less than 25 mg of agent per ml of fluid, a poorly soluble 
agent is one that dissolves in the range of about 25 mg to 150 mg of agent 
per ml of fluid, a soluble agent dissolves about 150 mg to 600 mg of agent 
per ml of fluid. While the presently preferred embodiments have been 
described with reference to poorly or very soluble agents, it is to be 
understood the device can be used to deliver other agents. 
Typical methods used for the measurement of solubility are chemical and 
electrical conductivity. Details of various methods for determining 
solubilities are described in United States Public Health Service 
Bulletin, No. 67 of the Hygienic Laboratory; Encyclopedia of Science and 
Technology. Vol. 12, pages 542 to 556, 1971, published by McGraw-Hill, 
Inc,; and Encyclopedia Dictionary of Physics, Vol. 6, pages 547 to 557, 
1962, published in Pergamon Press, Inc. 
The interaction of the hydrophilic polymer-drug interface can be 
ascertained by placing a film formed of a hydrophilic polymer in contact 
with an aqueous solution containing an active agent, and sometimes an 
osmagent, and observing the modification of the polymer at the 
polymer-aqueous environment. The surface of the polymer should be modified 
in situ during operation of the device. If a precipitate forms along the 
outer surface of the polymer, the polymer and the solution are suitable 
for operating the compartment of the device. A representative procedure 
that can be used consists in measuring the percent weight gain for various 
polymers immersed in a saturated solution of a drug or an osmagent. The 
procedure broadly indicates interface absorption activity. That is, if 
there is little absorption by the polymer, there is correspondingly a 
little gain in weight and the polymer is suitable for the purpose. 
Similarly, if there is a large gain in weight indicating a large volume 
absorbed, the polymer is not preferred for the purpose. FIG. 4 of U.S. 
Pat. 4,327,725 represents the percent weight gain for 4 polymers (A is 
Klucel H.RTM. polymer; B is Polyox COAG.RTM. polymer; C is 
Carbopol-934.RTM. polymer; and D is Na Carbopol-934.RTM. polymer) immersed 
in a saturated solution of NaCl as a function of the imbibition pressure 
of the polymer. Polymer imbibition pressure of any given hydrophilic 
polymer can be determined according to the procedure outlined in Cortese 
et al U.S. Pat. No. 4,327,735 column 10, line 67 to column 12, line 24, 
which is incorporated herein by reference. 
The device of the invention is manufactured by standard techniques. For 
example, in one embodiment, the agent and other ingredients that may be 
housed in one area of the compartment adjacent to the passageway, are 
pressed into a solid possessing dimension that corresponds to the internal 
dimensions of the area of the compartment the agent will occupy, or the 
agent and other ingredients and a solvent are mixed into a solid or 
semisolid form by conventional methods such as ballmilling, calendering, 
stirring or rollmilling, and then pressed into a preselected shape. Next, 
a layer of a hydrophilic polymer is placed in contact with the layer of 
agent in a like manner, and the two layers surrounded with a semipermeable 
wall. The layering of agent formulation and hydrophilic polymer can be 
fabricated by conventional two-layer press techniques. The wall can be 
applied by molding, spraying or dipping the pressed shapes into a wall 
forming material. Another and presently preferred technique that can be 
use for applying the wall is the air suspension procedure. This procedure 
consists of suspending and tumbling the pressed agent and dry hydrophilic 
polymer in a current of air and a wall forming composition until the wall 
is applied to the agent-hydrophilic polymer composite. The air suspension 
procedure is described in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., 
vol. 48, pages 451 to 459, 1979; and ibid, Vol. 49, pages 82 to 84, 1960. 
Other standard manufacturing procedures are described in Modern Plastics 
Encyclopedia, Vol. 46, pages 62 to 70, 1969; and in Pharmaceutical 
Sciences, by Remington, Fourteenth Edition, pages 1626 to 1678, 1970, 
published by Mack Publishing Company, Easton, Pa. 
Exemplary solvents suitable for manufacturing the wall include inorganic 
and organic solvents that do not adversely harm the wall forming material, 
and the final device. The solvents broadly include members selected from 
the group consisting of aqueous solvents, alcohols, ketones, esters, 
ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, 
aromatics, heterocyclic solvents, and mixtures thereof. Typical solvents 
include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, 
butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl 
acetate, methyl isobutyl ketone, methyl propyl ketone., n-hexane, 
n-heptane, ethylene glycol monoethyl ether, ethelene glycol monoethyl 
acetate, methylene dichloride, ethylene dichloride, propylene dichloride, 
carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl 
ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, 
naphtha, 1,4-dioxane, tetrahydrofuran, diglycol methyl ether, water and 
mixtures thereof such as acetone and water, acetone and methanol, acetone 
and ethyl alcohol, methylene dichloride and methanol, and ethylene 
dichloride and methanol, and mixtures thereof. 
The expression "passageway" as used herein comprises means and methods 
suitable for releasing the agent from the system. The expression includes 
one or more aperture, orifice or bore through wall 12 formed by mechanical 
procedures, or by eroding an erodible element, such as a gelatin plug, in 
the oral cavity. In cases where the semipermeable membrane is sufficiently 
permeable to the passage of beneficial agent/drug, the pores in the 
membrane may be sufficient to release the agent/drug in therapeutically 
effective amounts. In such cases, the expression "passageway" refers to 
the pores within the membrane wall even though no bore or other orifice 
has been drilled therethrough. A detailed description of osmotic 
passageways and the maximum and minimum dimensions for a passageway are 
disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899, the disclosures of 
which are incorporated herein by reference. Preferably, 1 to 2 passageways 
17 are provided in device 10 as shown in the Figures. 
The expressions "extended period of time" and "extended delivery period" as 
used herein generally refers to periods greater than about 0.5 hours, 
preferably about 0.5 to 12 hours, more preferably about 0.5 to 6 hours, 
most preferably about 1-4 hours. 
The following examples are merely illustrative of the present invention and 
should not be considered as limiting the scope of the invention in any 
way. 
EXAMPLE 1 
An osmotic therapeutic device for the controlled and continuous release 
into the oral cavity of the beneficial antifungal drug nystatin was made 
as follows: 43 mg of nystatin, 193 mg of polyethylene oxide (Polyox N-10), 
13 mg of hydroxy propyl methyl cellulose (HPMC E-5), 3 mg of sodium 
saccharin, 13 mg of oil of anise and 1 mg of magnesium stearate are mixed 
thoroughly and pressed in a Manesty Layer Press with a 5/8 inch oval punch 
using a pressure head of 2 tons to produce a layer of the drug 
composition. The nystatin had a natural yellow color while the remaining 
ingredients had a natural white color. Accordingly, the drug composition 
had a natural pale yellow color. The oil of anise was added as a flavoring 
agent to mask the objectionable bitter taste of the nystatin. 
Next, the driving layer of the device was formulated by mixing 114 mg of 
polyethylene oxide (Polyox Coag), 52 mg NaCl, 9 mg hydroxy propyl methyl 
cellulose (HPMCE-5), 2 mg Fe.sub.2 O.sub.3 as a colorant and 1 mg of 
magnesium stearate. The formulation was added to the Manesty Layer Press 
and pressed to form a layer of hydrophilic polymer in contact with the 
drug layer. The hydrophilic polymer driving layer had a reddish-brown 
color due to the ferric oxide. 
Next, a semipermeable wall was formed by blending 24 g of cellulose acetate 
having an acetyl content of 39.8% with 1103 ml of acetone, 97 ml of water 
and 16 g of hydroxy propyl cellulose (KLUCEL EF), and spray coating the 
two layered compartment forming member in an air suspension machine having 
a 0.4 kg charge until a 6 mil thick semipermeable wall surrounds the 
compartment. The coated device was dried for 72 hours at 35.degree. C., 
and then two 25 mil passageways were laser drilled through the 
semipermeable wall to connect the layer of drug with the exterior of the 
device. The KLUCEL component of the wall material made the wall 
sufficiently translucent to clearly see the yellow drug layer and the 
reddish-brown hydrophilic polymer layer. Accompanying FIG. 5 depicts the 
cumulative amount of nystatin released by the device when retained in the 
mouth of a human over a period of 3 hours and compares the nystatin 
release profile with the profiles of the nystatin delivery devices 
described in Comparative Examples 1 and 2. 
COMATIVE EXAMPLE 1 
A chewing gum containing nystatin is prepared in accordance with Example 1 
of U.S. Pat. No. 4,238,475 with the following exceptions. Each stick of 
gum is loaded with 43 mg of nystatin (the same dose of nystatin utilized 
in Example 1) instead of 5 mg nystatin. Thus, the weight percent of 
nystatin in each stick of chewing gum is about 1.5 wt % rather than 0.18 
wt %. all other ingredients are prepared as in Example 1 of U.S. Pat. No. 
4,238,475. Accompanying FIG. 5 depicts the cumulative amount of nystatin 
released into the mouth of a human chewing the gum over a period of 3 
hours. 
COMATIVE EXAMPLE 2 
A nystatin containing chewing gum is prepared as in comparative Example 1 
except that the conventional chewing gum base is replaced with ethylene 
vinyl acetate having a vinyl acetate content of 51%. The dose of nystatin 
in each stick of gum is again 43 mg or about 1.5 wt %. The gum is chewed 
by a human for a period of 3 hours and the cumulative amount of nystatin 
released is shown in FIG. 5. 
A comparison of the three nystatin delivery profiles plotted in FIG. 5 
shows that the device of the present invention releases nystatin into the 
oral cavity at a substantially constant delivery rate. This is shown by 
the substantially straight line release profile for Example 1. By 
comparison, the chewing gums of Comparative Examples 1 and 2 have a 
tendency to release a major portion of the nystatin within the first 20 
minutes of chewing. For Comparative Example 1, the chewing gum releases 
about 75% of the total nystatin dose in the first 20 minutes. For the EVA 
base gum of Comparative Example 2, approximately 40% of the nystatin dose 
is delivered within the first 20 minutes. The curves shown in FIG. 5 
illustrate that the chewing gums of Comparative Examples 1 and 2 are 
ill-suited for delivering nystatin to the oral cavity over periods of 
greater than about 1 hour. 
EXAMPLE 2 
An osmotic therapeutic device manufactured in the form of an oral delivery 
device for delivering chlorhexidine diacetate into the oral cavity was 
manufactured as follows: first a 150 mg composition comprising 3.7% 
chlorhexidine diacetate, 90.8% polyethylene oxide (Polyox N-10), 5% 
hydroxy propyl methyl cellulose (HPMC E-5) and 0.5% magnesium stearate was 
prepared by blending the four ingredients into a homogenous blend, and 
then pressed into a solid mass in a commercially available Manesty 
tableting machine set to a Stoke's hardness of 7 kg. The resulting 
drug-containing layer had a white color. 
Next, a 100 mg composition comprising 68.5% polyethylene oxide having a 
molecular weight of about 5,000,000 (Polyox Coag), 20% NaCl, HPMC E-5, 5% 
Carbomer 934 P, 1% ferric oxide colorant and 0.5% magnesium stearate was 
added to the tableting machine and pressed into a solid mass in contact 
with the drug-containing layer. The hydrophilic polymer layer had a 
reddish-brown color, due to the ferric oxide, providing a good color 
contrast with the white drug-containing layer. Then, the two layered mass 
was coated in a standard air suspension machine with a semipermeable 
polymeric wall formed from a 4% solids solution consisting of 60 wt % 
cellulose acetate having an acetyl content of 39.8%, in a solvent 
consisting of 90% acetone and 10% water, and 40 wt % hydroxy propyl 
cellulose (KLUCEL EF). The resulting semipermeable wall had a thickness of 
5 mils. The KLUCEL component of the wall material made the wall 
translucent, making it possible to see both the white drug-containing 
layer and the reddish-brown hydrogel layer within the inner compartment of 
the device. Finally, one osmotic passageway, having a diameter of 25 mils, 
was drilled through the wall facing the chlorhexidine-containing layer for 
delivering it from the device. 
EXAMPLE 3 
An oral osmotic therapeutic device for delivering ibuprofen is manufactured 
by following the procedure of Example 2, with all conditions and 
procedures as described, except in this example the layer of drug 
formulation comprises 20.5% ibuprofen, 66.5% Polyox N-10, 5% HPMC E-5, 
7.5% sodium carbonate and 0.5% magnesium stearate. The ibuprofen 
containing layer has a white color. The hydrophilic polymer layer 
comprises 64.3% Polyox Coag, 29.2% NaCl, 5% HPMC E-5, 1% ferric oxide 
colorant, and 0.5% magnesium stearate: The resulting hydrogel layer has a 
reddish-brown color. The translucent semipermeable wall is 5 mils thick 
and comprises 60% cellulose acetate having an acetyl content of 39.8% and 
40% Klucel EF, formed from a solvent consisting essentially of 90% acetone 
and 10% water. One passageway with a diameter of 25 mils is drilled in the 
side of the device adjacent the ibuprofen-containing layer. 
Unlike in Example 2, following drilling of the passageway, the device is 
overcoated with a mixture comprising 20 wt % ibuprofen and 80 wt % HPMC. 
The overcoating layer has a thickness of 3 mils. The ibuprofen containing 
overcoat provides a loading dose which is quickly delivered to the patient 
upon retention in the mouth. Generally, the overcoat layer will be 
completely removed by patient sucking within about 15 to 30 minutes. This 
is especially useful in cases where there is an initial delay between the 
time when the device is placed in the mouth of the patient and the time 
when the device begins pumping drug. 
While there have been described and pointed out features of the invention 
as applied to the presently preferred embodiments, those skilled in the 
art will appreciate that various modifications, changes, additions and 
omissions in the systems illustrated and described can be made without 
departing from the spirit and scope of the invention as defined in the 
appended claims.