Osmotic system for the controlled and delivery of agent over time

An osmotic system for delivering a beneficial agent is disclosed. The system comprises a wall surrounding an agent compartment and an osmagent compartment separated by a film and has a passageway through the wall for delivering agent from its compartment. The wall is formed of a material permeable to the passage of an external fluid and impermeable to the passage of agent and osmagent. The film is formed of a material impermeable to the passage of agent and osmagent and movable from an original to an expanded state. The agent compartment contains an agent that is soluble in the fluid and exhibits an osmotic pressure gradient across the wall against the fluid, or the compartment contains an agent that has limited solubility in the fluid and exhibits a limited osmotic pressure gradient across the wall against fluid. The osmagent compartment contains an osmagent that exhibits an osmotic pressure gradient across the wall against the fluid. In operation, agent is delivered from the system through the passageway by fluid being imbibed through the wall into the osmagent compartment urging it to increase in volume and expand the film and correspondingly diminishing the volume of the agent compartment, whereby agent is released at a rate controlled by the permeability of the wall, the osmotic pressure gradient across the wall, and the expansion of the film over a prolonged period of time.

FIELD OF THE INVENTION 
This invention pertains to an osmotic system. More particularly, the 
invention relates to an osmotic system manufactured in the form of an 
osmotic device. The system comprises a semipermeable wall surrounding a 
beneficial agent compartment and an osmagent compartment separated from 
each other by an expandable film. The osmagent compartment can increase 
its volume while correspondingly diminishing the volume of the agent 
compartment, thereby improving the delivery kinetics of the system and the 
amount of agent released from the system over a prolonged period of time. 
BACKGROUND OF THE INVENTION 
Osmotic systems manufactured in the form of osmotic devices for delivering 
a beneficial agent to an environment of use are known to the art in U.S. 
Pat. Nos. 3,845,770 and 3,916,899. The systems disclosed in these patents 
comprise a semipermeable wall that surrounds a compartment containing an 
agent. The wall is permeable to an external fluid, substantially 
impermeable to agent, and thee is a passageway through the wall for 
delivering the agent from the system. These systems 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 a solution of soluble agent, or a solution of an 
osmotic attractant containing insoluble agent which solution in either 
operation is dispensed from the system. These systems are extraordinarily 
effective for delivering both 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. While the above systems are outstanding and represent a pioneer 
advancement in the delivery art, and while they are endowed with ideal 
delivery kinetics useful for delivering numerous beneficial agents at a 
controlled and continuous rate to environments of use, there is an 
occassional instance where the delivery kinetics of the system can be 
unexpectedly improved to lead to more desirable results. For example, the 
rate of agent delivered by the system is constant for most agents as long 
as excess solid agnt is present in the system with its rate declining 
parabolically towards zero as the agent's concentration decreases below 
saturation. That is, both the solubility and the density of the agent 
influence the amount of agent delivered at a constant rate, and that 
amount delivered at a declining rate is proportional to the solubility of 
the agent and inversely proportional to its density. These actions often 
make it difficult to utilize the full specific therapeutic effect of an 
agent, particularly when the agent is very soluble in the fluid and 
concomitantly a portion of the agent cannot be delivered at a constant 
rate over a prolonged period of time, and when the agent has limited 
solubility in the fluid. These latter agents do not readily form solutions 
or suspensions with the fluid and they exhibit limited osmotic pressure 
gradients across the wall, which properties make it difficult to dispense 
them for utilizing their full therapeutic effect. The prior art improved 
the delivery kinetics for both of these agents by mixing with the agents 
an osmagent that is coadministered with the agent. Additional prior art 
osmotic devices are seen in U.S. Pat. No. 3,760,804. This patent discloses 
a device having a rigid housing member formed of an impermeable material 
and having a movable separation therein forming two chambers. While this 
device operates successfully for its intended purpose, its use is limited 
because the agent must be in a semi-solid form, movable separators are 
hard to make and leaks often occur at the separation between the 
compartments. In U.S. Pat. No. 3,760,805, an osmotic device is disclosed 
consisting of a rigid housing member containing two bags. One bag is made 
of an impervious material housing a solution, semi-solid, gel or paste 
containing an agent, and the other bag is made of a permeable material 
housing an osmotic solute. While this device represents an advancement in 
the art, its use is limited because the agent must be in a liquid-like 
state. This precludes high agent loading because the liquid occupies space 
in the bag. Also, solid agents cannot be delivered from the device because 
the wall of the bag housing the agent is impermeable to the passage of 
fluid, which structural feature prevents both inhibition of fluid and 
mixing of the solid agent with fluid. The fluid is needed as a carrier for 
delivering agent in solution or suspension from the system. In U.S. Pat. 
No. 3,760,809 there is disclosed an osmotic device formed of two helical 
compartments consisting of one formed of an impermeable material separated 
by a sliding barrier plug from a second helical compartment. Also, U.S. 
Pat. No. 3,929,132 discloses an osmotic device made of a rigid housing 
member having a removable dispensing head, a threaded end, an internal 
agent chamber made with impermeable walls, an osmotic solute chamber 
having a porous membrane support for a semipermeable membrane, with the 
chambers separated by a movable barrier. The device of this patent 
operates in a manner similar to the device of U.S. Pat. No. 3,760,804 and 
has the same limitations. The present invention improves the delivery 
kinetics of the system and increases the amount of agent delivered 
therefrom by using an agent chamber formed with a semipermeable wall 
thereby making possible the housing of larger amounts, the mixing, and the 
delivery of solid agent from the system. The invention also uses the 
osmagent in a separate chamber for delivery of substantially pure agent 
from the system. A mathematical presentation pertaining to the instant 
subject matter is known in J. Pharm. Sci., Vol. 64, No. 12, pages 1987 to 
1991, 1975. 
OBJECTS OF THE INVENTION 
Accordingly, it is an immediate object of this invention to provide an 
improved osmotic system for the controlled and continuous delivery of a 
beneficial agent over a prolonged period of time which system improves the 
systems known to the prior art. 
Yet another object of the invention is to provide an osmotic system having 
an agent compartment and a separate compartment that operates to diminish 
the volume of the agent compartment, thereby maintaining the solution in 
the agent compartment saturated with agent for its release over time. 
Still another object of the invention is to provide an osmotic system 
having a compartment that continuously increases in volume while 
correspondingly diminishing the volume of an adjacent agent compartment 
for maintaining excess solid agent in solution for its constant release 
over time. 
Still a further object of the invention is to provide an osmotic system 
that can continuously maintain substantially the major amount of agent 
present in a saturated solution with excess solid dispersed therein 
through the agent's release from the system. 
Yet still a further object of the invention is to provide an osmotic 
therapeutic system that can administer a complete pharmaceutical regimen 
comprising very soluble or limited soluble agents at a controlled and 
continuous rate to animals including humans, for a particular time period, 
the use of which requires intervention only for initiation and possibly 
termination of the regimen. 
Yet still another object of the invention is to provide an osmotic system 
having a compartment, containing the agent, which imbibes fluid 
osmotically, thereby formulating the agent in semi-solid form to be 
dispensed at a rate controlled by the osmagent compartment. 
Yet still another object of the invention is to provide an osmotic system 
having a comaprtment containing the agent in a base which melts in the 
environment of use such that the agent is dispensed from the system in the 
base by osmotic imbibition of the osmagent compartment. 
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. 
SUMMARY OF THE INVENTION 
This invention concerns an osmotic system for dispensing an active agent to 
a environment of use. The system comprises a semipermeable wall 
surrounding two adjoining compartments and has a passageway through the 
wall communicating with one of the compartments and the exterior of the 
system. The compartment with the passageway contains an agent that is 
soluble in an external fluid and exhibits an osmotic pressure gradient 
across the wall against the fluid, or it contains an agent having limited 
solubility in the fluid and exhibits a limited osmotic pressure gradient 
across the wall against the fluid. The other compartment contains a 
compound that is soluble in the fluid and exhibits an osmotic pressure 
gradient across the wall against the fluid. The compartments are separated 
by a contiguous film formed as a wall of one of the compartments and made 
of a material impermeable to agent and compound that can expand from a 
rested to an expanded state. Agent is released from the system by the 
combined action of fluid being imbibed through the wall into the 
compartment containing agent to product a solution, suspension, or paste 
containing agent, and by fluid being imbibed through the wall into the 
compartment containing compound causing it to increase in volume and 
expand, thereby exerting a force on the film urging it to expand into the 
adjacent compartment and diminish its volume, whereby agent is released at 
a rate controlled by the permeability of the wall and the osmotic pressure 
gradient across the wall and the expansion of the film over a prolonged 
period of time.

In the drawings and specification, like parts in related figures are 
identified by like numbers. The terms appearing earlier in the 
specification and in the description of the drawings, as well as 
embodiments thereof, are further detailed elsewhere in the disclosure. 
DETAILED DESCRIPTION OF THE DRAWINGS 
Turning now to the drawings in detail, which are examples of various 
osmotic delivery systems of the invention, and which examples are not to 
be considered as limiting, one example of an osmotic delivery system 
manufactured in the form of an osmotic device is indicated in FIGS. 1A 
through 1F, considered together, by the numeral 10. The phrases "osmotic 
delivery system" and "osmotic delivery system in the form of an osmotic 
device" as used for the purpose of this invention, are used as functional 
equivalents and they also embrace the expressions "osmotic therapeutic 
system", "osmotic device", and "system". 
In FIGS. 1A through 1F, system 10 is seen comprised of a body 11 having a 
wall 12 that surrounds and forms a first compartment 13 and a second 
compartment 14, illustrated in FIGS. 1B through 1F in crosssection, and a 
passageway 15 that communicates with compartment 13 and the exterior of 
system 10. Compartment 13, as seen in FIG. 1B, in one embodiment contains 
an agent 16 that is soluble to very soluble in an external fluid 19, 
exhibits an osmotic pressure gradient across wall 12 against the fluid and 
is in direct communication with wall 12, or compartment 13 in another 
embodiment contains an agent 16 that has limited solubility or is 
substantially insoluble in fluid 19 and exhibits a limited, or it not 
exhibit any, osmotic pressure gradient across wall 12 against the fluid, 
and is in contact with the interior surface of semipermeable wall 12. When 
agent 16 has limited solubility or it is substantially insoluble in fluid 
19, 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. 
Compartment 14, as seen in FIG. 1B, in a prsently preferred embodiment 
contains an osmagent 17, which is an osmotically effective compound, that 
is soluble in fluid 19 and exhibits an osmotic pressure gradient across 
wall 12 against fluid 19, or compartment 14 can contain a plurality of 
osmagents 17 with each exhibiting the same or different osmotic pressure 
gradients across wall 12 against fluid 19. 
Compartments 13 and 14 of system 10 are separated by a contiguous film or 
membrane 18, seen in FIGS. 1B through 1F, for improving and assisting in 
regulating delivery and the amount of agent 16 from compartment 13. Film 
18 is free of passageways and it is formed of an expandable material that 
can move from an initial or rested position, seen in FIG. 1B, through a 
series of sequential changes as seen in FIGS. 1C through 1E, to form fully 
expanded film 18 as seen in FIG. 1F. 
Compartment 14 operates in cooperation with system 10, particularly 
compartment 13, to release agent 16 to the environment of use from system 
10. System 10 in one embodiment, releases agent 16 in compartment 13 and 
soluble in the external fluid by fluid being imbibed into compartment 13 
in a tendency towards osmotic equilibrium at a rate controlled by the 
permeability of wall 12 and the osmotic pressure gradient across wall 12 
to dissolve agent 16 which is osmotically pumped from system 10 through 
passageway 15 over a prolonged period of time. Compartment 14 operates to 
substantially insure that delivery of agent 16 from compartment 13 is 
constant over a prolonged period of time by two methods. First, 
compartment 14 operates to continuously concentrate agent 16 by imbibing 
fluid from compartment 13 through film 18 to keep the concentration of 
agent 16 from falling below saturation. Secondly, compartment 14 by 
imbibing external fluid 19 across wall 12 continuously increases its 
volume, thereby exerting a force on film 18 urging it to expand into and 
diminish the volume of compartment 13, thusly insuring continuous 
saturation of agent 16 in compartment 13. FIGS. 1C through 1F illustrate 
the expansion of film 18 with the accompanying increase in volume of 
compartment 14 along with the simultaneous, corresponding reduction in 
volume of compartment 13. Compartment 13 in a presently preferred 
embodiment, can contain various amounts of agent 16. Agent 16 can be 
present in large amounts as a solid, which is mixed with fluid imbibed 
into compartment 13 to form a solution or suspension for release from 
system 10. In this manner, compartment 13 operates as a formulation 
compartment and thereby makes possible (a) the housing of large amounts of 
agent and (b) increases the amount of agent delivered at a controlled rate 
from system 10. System 10, in another embodiment, releases agent 16 that 
has limited solubility in the fluid and is mixed with an osmagent by fluid 
being imbibed through wall 12 into compartment 13 in a tendency towards 
osmotic equilibrium at a rate controlled by the permeability of wall 12 
and the osmotic pressure gradient across wall 12 to continuously dissolve 
the osmagent and form a solution containing agent 16 that is pumped from 
system 10 through passageway 15. In this embodiment, compartment 14 
operates as described supra. In other embodiments, agent 16 can be present 
as a gel, paste or semi-solid which formulation is released by the 
compartments of the system operating as a unit system as described above. 
A detailed mathematical presentation of the operation of system 10 
including compartment 13 and compartment 14, appears later in the 
specification. 
Wall 12 of system 10 is comprised of a semipermeable material that is 
permeable to the passage of an external fluid and it is essentially 
impermeable to agent 16, osmagent 17, and other ingredients housed in 
compartments 13 and 14. Film 18 of system 10 is formed of a material that 
is deformable, either permeable or impermeable to the passage of fluid, 
and in both instances, impermeable to the passage of agent and osmagent; 
and, it can undergo expansion over a prolonged period of time. Wall 12 and 
film 18 can be formed of synthetic or naturally occurring materials and a 
detailed description of these materials appears later in the 
specification. 
System 10 of FIGS. 1A through 1F can be made into many embodiments 
including the presently preferred embodiments for oral use, that is, for 
releasing either a locally or systemically acting therapeutic agent in the 
gastrointestinal tract over a prolonged period of time. Oral system 10 can 
have various conventional shapes and sizes such as round with a diameter 
of 3/16 inch to 1/2 inch, or it can be shaped like a capsule having a 
range of sizes from triple zero to zero, and from 1 to 8. In these forms, 
system 10 can be adapted for administering agent to numerous animals, warm 
blooded mammals, avians and fishes. 
FIGS. 2 and 3 represent additional embodiments of system 10 manufactured 
according to the invention and designed for dispensing agent 16 to 
numerous environments of use. In FIGS. 2 and 3, system 10 is seen in 
opened section and it is similar to system 10 of FIGS. 1A through 1F, with 
each system comprising a body 11 having a wall 12 that surrounds an agent 
compartment 13 and an osmagent compartment 14, with compartment 13 having 
a passageway 15 that communicates with the exterior of system 10. 
Compartments 13 and 14 both house the ingredients housed in FIGS. 1A 
through 1F. In FIGS. 2 and 3, compartments 13 and 14 are separated by 
movable film 18 that forms the entire barrier member between the 
compartments. System 10 of FIGS. 2 and 3 operate as described above with 
the added embodiment that all of film 18 can be used for increasing the 
volume of compartment 14, and that all of film 18 can be used for 
decreasing the volume of compartment 13, thereby insuring the controlled, 
continuous and constant release of agent 16 from compartment 13 to the 
exterior of system 10. 
FIG. 4 shows an osmotic system 10 designed for placement in a vagina. 
System 10 has an elongated, cylindrical, self-sustaining shape with a 
rounded lead end 20, a trailing end 21, and it is equipped with a manually 
controlled cord 22 for easily removing system 10 from a vagina. System 10 
is structurally identical with system 10 as described above and it has a 
film 18 that operates in a like manner by being capable of expanding from 
18a through 18e. System 10 of FIG. 4 in one embodiment contains a drug 16 
designed for absorption by the vaginal mucosa to produce a local or 
systemic effect, and in another embodiment it contains an odor reductant 
that emits an odor counteracting scent or fragrence in the vagina. 
Referring to FIG. 5, an ocular therapeutic system 10 is seen in an eye 25 
for administering drug at an osmotically metered dosage rate thereto. In 
FIG. 5, eye 25 is comprised of an upper eyelid 26 with eyelashes 27 and 
lower eyelid 28 with eyelashes 29. Eye 25 anatomically is comprised of an 
eyeball 30 covered for the greater part by sclera 31 and at its center 
area by cornea 32. Eyelids 26 and 28 are lined with an epithelial membrane 
or palpebral conjunctiva, and sclera 31 is lined with a bulbar conjunctiva 
that covers the exposed surface of eyeball 30. Cornea 30 is covered with a 
transparent epithelial membrane. The portion of the palpebral conjunctiva 
which lines upper eyelid 26 and the underlying portion of the bulbar 
conjunctiva defines an upper cul-de-sac, while that portion of the 
palpebral conjunctiva which lines lower eyelid 28 and the underlying 
portion of the bulbar conjunctiva defines a lower cul-de-sac. Ocular 
osmotic system 10, seen in broken lines, is designed for placement in the 
upper or lower cul-de-sac. System 10 is seen in the lower cul-de-sac and 
it is held in place by the natural pressure of lower eyelid 28. System 10 
contains an ophthalmic drug for release to eye 25 at a controlled and 
continuous rate over a prolonged period of time. 
Ocular system 10, manufactured according to the inventive principles 
described supra, can have any geometric shape that fits comfortably in the 
cul-de-sac. Typical shapes include, ellipsoid, bean, banana, circular, 
ring, rectangular, doughnut, crescent and half-ring shaped systems. In 
cross-section, the systems can be doubly convex, concavo-convex, 
rectangular and the like, as the device in use will tend to conform to the 
shape of the eye. The dimensions of an ocular system can vary widely with 
the lower limit governed by the amount of drug to be administered to the 
eye as well as the smallest sized system that can be placed into the eye. 
The upper limit on the size of the system is governed by the space 
limitation in the eye consistent with comfortable retention in the eye. 
Satisfactory systems have a length of 4 to 20 millimeters, a width of 1 to 
15 millimeters. The ocular system can contain from 0.15 micrograms to 100 
milligrams of drug, or more, and it is made from materials non-toxic to 
the eye. 
While FIGS. 1 through 5 are illustrative of various systems that can be 
made according to the invention, it is to be understood these systems are 
not to be construed as limited, as the system can take a wide variety of 
shapes, sizes and forms for delivering agent to different environments of 
use. For example, the system includes buccal, implant, anal, rectal, 
artificial gland, cervical, intrauterine, ear, nose, dermal, subcutaneous, 
and blood systems. The systems also can be sized, shaped and adapted for 
delivering an active agent in streams, aquariums, fields, factories, 
reservoirs, laboratory facilities, hot houses, transportation means, naval 
means, military means, hospitals, veterinary clinics, nursing homes, 
farms, zoos, sickrooms, chemical reactions, and other environments of use. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the practice of the invention, it has now been found 
that osmotic delivery system 10 can be manufactured with a wall 12 formed 
of a material that does not adversely affect the agent and osmagent, an 
animal body, or other host, and is permeable to an external fluid 16 such 
as water and biological fluids while remaining essentially impermeable to 
agents, including drugs, osmagents, and the like. The selectively 
permeable materials forming wall 12 are insoluble in body fluids, and they 
are non-erodible, or they can be made to bioerode after a predetermined 
period with bioerosion corresponding to the end of the agent release 
period. Typical materials for forming wall 12 include semipermeable 
materials known to the art as osmosis and reverse osmosis membranes such 
as cellulose acetate, cellulose triacetate, agar acetate, amylose 
triacetate, beta glucan acetate, cellulose diacetate, acetaldehyde 
dimethyl acetate, cellulose acetate ethyl carbamate, polyamides, 
polyurethane, sulfonated polystyrenes, cellulose acetate phthalate, 
cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose 
acetate dimethylaminoacetate, cellulose acetate ethyl carbamate, cellulose 
acetate chloroacetate, cellulose dipalmitate, 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, selectively permeable polymers formed by the coprecipitation of 
a polycation and a polyanion as disclosed in U.S. Pat. Nos. 3,173,876; 
3,276,586; 3,541,005; 3,541,006; and 3,546,142. Generally, semipermeable 
materials useful for forming wall 12 will have a fluid permeability of 
10.sup.-5 to 10.sup.-1 (cc.mil/cm.sup.2.hr.atm) expressed per atmosphere 
of hydrostatic or osmotic pressure difference across wall 12 at the 
temperature of use. Other suitable materials are known to the art in U.S. 
Pat. Nos. 3,845,770 and 3,916,899. 
Film 18 of system 10, also known as membrane 18, is formed from the above 
materials and it is made expandable by (1) controlling its thickness to 
about 2 to 6 mils, and (2) by optionally adding from 0.01% to 40% of a 
film expansion agent that imparts flexibility, deformability and expansion 
properties thereto. Generally, a film expansion agent, or a multiplicity 
of film expansion agents are added to the material forming film 18 when 
the material has a moderate to high degree of substitution or a moderate 
to high acyl content, usually 35 to 43%. Suitable agents include 
polyhydric alcohols and derivatives thereof, such as polyalkylene glycols 
of the formula H-(O-alkylene).sub.n --OH wherein the bivalent alkylene 
radical is straight or branched chain and has from 1 to 10 carbon atoms 
and n is 1 to 500 or higher. Typical glycols include polyethylene glycols 
300, 400, 600, 1500, 1540, 4000 and 6000 of the formula H--(OCH.sub.2 
CH.sub.2).sub.n --OH wherein n is respectively 5, 5.7, 8.2 to 9.1, 12.5 to 
13.9, 29 to 36, 29.8 to 37, 68 to 84, and 158 to 204. Other polyglycols 
include low molecular weight glycols such as polypropylene, polybutylene 
and polyamylene. 
The film expansion agents in another embodiment include 
poly(.alpha.,.omega.)-alkylenediols wherein the alkylene is straight or 
branched chain of from 2 to 10 carbon atoms such as poly(1,3)-propanediol, 
poly(1,4)-butanediol, poly(1,5)-pentanediol and poly(1,6)-hexanediol. The 
diols also include aliphatic diols of the formula HOC.sub.n H.sub.2n OH 
wherein n is from 2 to 10 and the diols are optionally bonded to a 
non-terminal carbon atom such as 1,3-butylene glycol, 1,4-pentamethylene 
glycol, 1,5-hexamethylene glycol and 1,8-decamethylene glycol; and 
alkylenetriols having 3 to 6 carbons atoms such as glycerine, 
1,2,3-butanetriol, 1,2,3-pentanetriol, 1,2,4-hexanetriol, 
1,3,6-hexanetriol, and mixtures thereof. 
Other film or membrane expanding agents include esters and polyesters of 
alkylene glycols of the formula HO--(alkylene-O).sub.n --H wherein the 
divalent alkylene radical includes the straight chain groups and the 
isomeric forms thereof having from 2 to 6 carbons and n is 1 to 14. The 
esters and polyesters are formed by reacting the glycol with either a 
monobasic or dibasic acid. Exemplary agents are ethylene glycol 
dipropionate, ethylene glycol butyrate, ethylene glycol diacetate, 
triethylene glycol diacetate, butylene glycol dipropionate, polyester of 
ethylene glycol with succinic acid, polyester of diethylene glycol with 
maleic acid, and polyester of triethylene glycol with adipic acid. 
Exemplary film expansion agents suitable for the present purpose 
generically include agents that lower the temperature of the second-order 
phase transition of the film forming materials or the elastic modulus 
thereof, increase the workability of the film, its flexibility, and its 
permeability to fluid. Agents operable for the present purpose include 
both cyclic and acyclic agents. Typical agents are those selected from the 
group consisting of phthalates, phosphates, citrates, adipates, tartrates, 
sebacates, succinates, glycolates, glycerolate, benzoates, myristates, 
sulfonamides, and halogenated phenyls. 
Exemplary film expanders further include dialkyl phthalates, dicycloalkyl 
phthalates, diaryl phthalates and mixed alkyl-aryl phthalates as 
represented by dimethyl phthalate, dipropyl phthalate, 
di(2-ethylhexyl)phthalate, di-isopropyl phthalate, diamyl phthalate and 
dicapryl phthalate, alkyl and aryl phosphates such as tributyl phosphate, 
trioctyl phosphate, tricresyl phosphate, trioctyl phosphate, tricresyl 
phosphate and triphenyl phosphates; alkyl citrate and citrate esters such 
as tributyl citrate, triethyl citrate, and acetyl triethyl citrate; alkyl 
adipates such as dioctyl adipate, diethyl adipate and 
di(2-methoxyethyl)-adipate; dialkyl tartrates such as diethyl tartrate and 
dibutyl tartrate; alkyl sebacates such as diethyl sebacate, dipropyl 
sebacate and dinonyl sebacate; alkyl succinates such as diethyl succinate 
and dibutyl succinate; alkyl glycolates, alkyl glycerolates, glycol esters 
and glycerol esters such as glycerol diacetate, glycerol triacetate, 
glycerol monolactate diacetate, methyl phthayl ethyl glycolate, butyl 
phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol 
dibutyrate, triethylene glycol diacetate,, triethylene glycol dibutyrate 
and triethylene glycol dipropionate. Also, camphor, N-ethyl-(o- and 
p-toluene) sulfonamide, chlorinated biphenyl, benzophenone, 
N-cyclohexyl-p-toluene sulfonamide, and substituted epoxides. 
Suitable film expansion agents can be selected for blending with the film 
forming materials by selecting agents that have a high degree of solvent 
power for the materials, are compatible with the materials over both the 
processing and use temperature range, exhibit permanence as seen by a 
strong tendency to remain in the film, impart the desired properties, and 
are non-toxic to animals, including humans, avians, fishes and reptiles. 
Procedures for selecting an agent having the described characteristics are 
disclosed in the Encyclopedia of Polymer Science and Technology, Vol. 10, 
pages 228 to 306, 1969, published by John Wiley & Sons, Inc. 
The expression "passageway" as used herein comprises means and methods 
suitable for releasing the agent from the system. The expression includes 
aperture, orifice or bore through wall 12 formed by mechanical procedures, 
or by eroding an erodible element, such as gelatin plug, in the 
environment of use. 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 osmotically effective compounds 17 that can be used for the purpose of 
the invention include inorganic and organic compounds that exhibit an 
osmotic pressure gradient against an external fluid 19 across wall 12 and 
film 18. These compounds are known as osmagents. The osmagents, when 
present in compartment 13, are mixed with an agent that has limited 
solubility in external fluid with the osmagent forming a saturated 
solution when mixed with fluid containing agent that is osmotically 
delivered from the system. In agent 16 is soluble in the fluid, an 
osmagent is not needed and pure agent can therefore be delivered from the 
device. The osmagents are present in compartment 14 for: (a) imbibing 
fluid from compartment 13 to concentrate solution in compartment 13; and 
(b) for compartment 14 to fill and expand in volume with a corresponding 
collapse of compartment 13. The osmagents are used by homogenously or 
heterogenously mixing them or a mixture of osmagents with agent 16, either 
before they are charged into compartment 13, or by self-mixing after they 
are charged into compartment 13. In operation, these osmagents attract 
fluid into compartment 13 producing a solution of osmagents which is 
delivered from the system concomitantly transporting undissolved and 
dissolved agent 16 to the exterior of the system. The osmagents are 
present in compartment 14 independent of the presence of any other agent. 
Osmotically effective compounds 16 useful for the present purpose include 
magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, 
potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, 
potassium chloride, calcium carbonate, sodium sulfate, calcium sulfate, 
potassium acid phosphate, calcium lactate, d-mannitol, urea, inositol, 
magnesium succinate, tartaric acid, carbohydrates such as raffinose, 
succrose, glycose, and mixtures thereof. Osmagent 16 suitable for housing 
in compartment 14 also includes starches and carbohydrates such as algin, 
sodium alginate, potassium alginate, carrageenan, fucoridan, furcellaran, 
laminaran, hypnea, gum arabic, gum ghatti, gum karaya, locust bean gum, 
pectin, starch, 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, crystal, pellet, tablet, strip, powder, film or granule. The 
osmotic pressure .pi. in atomospheres ATM, of the osmagents suitable for 
the invention will be greater than zero ATM, generally from zero ATM up to 
500 ATM, or higher. 
The expressions "active agent" and "beneficial agent" as used herein 
broadly includes any compound, composition of matter or mixture thereof, 
that can be delivered from the system to produce a beneficial and useful 
result. The agent can be soluble in fluid 19 that enters the compartment 
13 and functions as its own osmotically effective solute, or it can have 
limited solubility in the fluid and be mixed with an osmotically effective 
compound 17 soluble in fluid that is delivered from the system. The active 
agent includes pesticides, herbicides, germicides, biocides, algicides, 
rodenticides, fungicides, insecticides, anti-oxidants, plant growth 
promoters, plant growth inhibitors, preservatives, anti-preservatives, 
disinfectants, sterilization agents, catalysts, chemical reactants, 
fermentation agents, foods, food supplements, nutrients, cosmetics, drugs, 
vitamins, sex sterilants, fertility inhibitors, fertility promoters, air 
purifiers, micro-organism attenuators, and other agents that benefit the 
environment of use. 
In the specification and the accompanying claims, the term "drug" includes 
an physiologically or pharmcologically active substance that produces a 
localized or systemic effect or effects in animals, including warm blooded 
mammals, humans and primates, avians, domestic household, sport or farm 
animals such as sheep, goats, cattle, horses and pigs, for administering 
to laboratory animals such as mice, rats and guinea pigs, to fishes, 
reptiles zoo and wild animals. The active drug that can be delivered 
includes inorganic and organic compounds without limitation, those 
materials that act on the central nervous system such as hypnotics and 
sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle 
relaxants, antiparkinson agents, analgesics, anti-inflammatory, local 
anesthetics, muscle contractants, anti-microbials, anti-malarials, 
hormonal agents including contraceptives, sympathomimetrics, diuretics, 
anti-parasitics, neoplastics, hypoglycemics, nutritional, fats, 
ophthalmic, electrolytes and diagnostic agents. 
Exemplary of drugs that are soluble or very soluble in water and can be 
delivered by the systems of this invention include prochlorperazine 
edisylate, ferrous sulfate, aminocaproic acid, potassium chloride, 
mecamylamine hydrochloride, procainamide hydrochloride, amphetamine 
sulfate, benzphetamine hydrochloride, isoproternol sulfate, 
methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol 
chloride, methacholine chloride, pilocarpine hydrochloride, atropine 
sulfate, methascopolamine bromide, isopropamide iodide, tridihexethyl 
chloride, phenformin hydrochloride, methylphenidate hydrochloride, and 
mixtures thereof. 
Exemplary of agents that have limited solubility or are very slightly 
soluble, or insoluble in water and biological fluids that can be delivered 
by the systems of this invention include diphenidol, meclizine 
hydrochloride, prochlorperazine maleate, thiethylperazine maleate, 
anisindione, diphenadione, erythrityl tetranitrate, dizoxin, 
isoflurophate, reserpine, azetazolamide, methazolamide, 
bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, 
phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl 
sulfisoxazole, erythromycin, and mixtures thereof, steroids including 
corticosteroids such as hydrocortisone, hydrocorticosterone acetate, 
cortisone acetate and triamcinolone, anhydrogens such as methyltesterone, 
esterogenic steroids such as 17.beta.-estradiol, ethinyl estradiol, 
ethinyl estradiol 3-methyl ether and estradiol, progestational steroids 
such as prednisolone, 17.alpha.-hydroxy-progesterone acetate, 
19-nor-progesteroine, norethindrone, progesterone, norethynodrel, and the 
like. 
The drug can also be in various chemical and physical forms, such as 
uncharged molecules, molecular complexes, pharmacologically acceptable 
acid addition and base addition salts such as hydrochlorides, 
hydrobromides, sulfate, laurylate, palmitate, phosphate, nitrate, borate, 
acetate, maleate, tartrate, oleate, and salicylate. For acidic drugs, 
salts of metals, amines or organic cations, for example quaternary 
ammonium can be used. Derivatives of drugs such as ester, ethers and 
amides can be used alone or mixed with other drugs. Also, a drug that is 
water insoluble can be used in a form that on its release from the device, 
such as prodrug, is converted by enzymes, hydrolyzed by body pH or other 
metabolic processes to the original form, or to a biologically active 
form. Agent 16 can be in the compartment 13 as a dispersion, paste, cream, 
gels, particle, granule, emulsion, suspension or powder. Also, agent 16 
can be mixed with a binder, dispersant, emulsifier, wetting agent or dye. 
The amount of agent 16 present in the system is initially in excess of the 
amount that can be dissolved in or mixed with the fluid that enters the 
compartment. Under this physical and chemical state when the agent is in 
excess, the system will osmotically operate to give a substantially 
constant rate of release. The rate of agent release pattern can also be 
varied by having different amounts of agent in the compartment to form 
solutions or mixtures containing different concentrations of agent for 
delivery from the system. Generally, the system can house from 0.05 ng to 
5 grams or more, with individual systems containing for example, 25 ng, 1 
mg, 5 mg, 250 mg, 500 mg, 1.5 g, and the like. The beneficial drugs are 
known to the art in Pharmaceutical Sciences, by Remington, 14th Ed., 1970, 
published by Mack Publishing Co., Easton, Penna; The Drug, The Nurse, The 
Patient, Including Current Drug Handbook, 1974-1976, by Falconer, et al, 
published by Saunder Company, Philadelphia, Penna; and, Medicinal 
Chemistry, 3rd Ed., Vol. I & II, by Burger, A., published by 
Wiley-Interscience, New York. 
The solubility or insolubility of agent 16 in an external fluid 19 can be 
determined by various art known techniques. One method consists in 
preparing a saturated solution comprising the external fluid plus the 
agent as ascertained by analyzing the amount present in a definite 
quantity of the fluid. A simple apparatus for this purpose consists of a 
test tube of medium size fastened upright in a water bath maintained at 
constant temperature and pressure, for example, one atmosphere, in which 
the fluid and agent are placed and stirred by a motor driven rotating 
glass spiral. After a given period of stirring, a definite weight of the 
fluid is analyzed and the stirring continued for an additional period of 
time. If the analysis shows no increase of dissolved agent after 
successive periods of stirrings, in the presence of excess solid agent in 
the fluid, the solution is saturated and the results are taken as the 
solubility of the product in the fluid. If the agent is soluble an added 
osmagent 17 is not needed; if the agent has limited solubility or it is 
insoluble in the fluid, then an osmagent 17 can optionally be incorporated 
into compartment 13. Numerous other methods are available for determining 
the solubility of an agent in a fluid. Typical methods used for measuring 
solubility include chemical analysis, ultra violet spectrometry, density, 
refractive index and electrical conductivity. Generally, for the purpose 
of this invention soluble to very soluble agents will dissolve in the 
range of from 150 mg to 900 mg of agent per milliliter of solution, and 
limited soluble to insoluble agents will dissolve in the range of 0.001 mg 
to 125 mg of agent per mililiter of fluid or less. While the invention has 
been described with particular reference to presently preferred 
embodiments including soluble and insoluble, it is understood the system 
of the invention can be used to deliver other agents having other kinds of 
solubilities. 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 by 
Pergamon Press, Inc. 
The systems of the invention are manufactured by standard techniques. For 
example, in one embodiment, agent 16 and optionally, osmagent 17 and other 
ingredients that may be housed in compartment 13 and a solvent are mixed 
into a solid, semi-solid or pressed state by conventional methods such as 
ballmilling, calendering, stirring or rollmilling and then pressed or 
tableted into a preselected shape. The film forming compartment 13 made of 
a material containing a film expansion agent can be applied thereto by 
molding, spraying or dipping the pressed shape into the film forming 
material. In another embodiment, a film can be cast, shaped to the desired 
dimensions that surround compartment 13 that is then filled with agent 16 
and closed. The system also can be manufactured with an empty compartment 
that is filled through the passageway. Compartment 14 is formed by 
pressing an osmagent 17 into a preselected shape which is then intimately 
attached to compartment 13. Finally, juxtaposed compartments 13 and 14 are 
surrounded with a semipermeable wall 12. Optionally, system 10 can be 
manufactured by first fabricating compartment 14 by pressing in a standard 
tableting machine an osmagent to form a predetermined shaped system which 
is then surrounded with a film forming material to form a closed 
compartment. Next, compartment 13 is formed by pressing an agent into a 
predetermined shape which pressed agent is joined to compartment 14. 
Finally, the two adjacent compartments are surrounded with a wall formed 
of a semipermeable material and a passageway is drilled through the wall 
into active agent compartment 13 to form osmotic system 10. 
Compartments 13 and 14 as described immediately above can be joined by 
methods well-known to the art, or they can be integrally formed as 
illustrated in the above figures. One operable method for joining the 
compartments consists in applying a dash or thin layer of a non-toxic 
adhesive to the joinable surfaces immediately preceeding their alignment 
into a working structure. Adhesives suitable for the present purpose 
include semipermeable silicon glue, cellulose nitrate, cellulose acetate, 
vinyl acetate and vinyl chloride adhesives, acrylic resins, aldehyde 
resins, water soluble gums, aqueous dispersions of paraffins, monomeric 
esters of .alpha.-cyanoacrylic acid, ureas, and the like. These adhesives 
are disclosed to the art in U.S. Pat. Nos. 3,547,771; 3,552,994; 
3,598,781; 3,627,559; 3,627,609; 3,755,044; and 3,759,264; in West Germany 
Pat. No. DT 2,009,968; and in British Pat. No. 577,735. The compartments 
also can be joined by other methods including heat sealing, pressing, 
consecutively casting the compartments in a dual cavity mold, overlaying, 
and the like. 
The walls and films forming the system can be joined by various techniques 
such as high frequency electronic sealing that provides clean edges and 
firmly formed walls and films, and, a presently preferred technique that 
can be used is the air suspension procedure. This procedure consists in 
suspending and tumbling the agent or osmagent in a current of air and a 
wall forming, or film forming, composition until the wall or film is 
applied to the agent or osmagent. The air suspension procedure is 
well-suited for independently forming the walls and films. The air 
suspension procedure is described in U.S. Pat. No. 2,799,241; in J. Am. 
Pharm. Assoc., Vol. 48, pages 451 to 459, 1959; and ibid., Vol. 49, pages 
82 to 84, 1960. Other wall and film forming techniques such as pan coating 
can be used in which the materials are deposited by successive spraying of 
the polymer solution on the agent or osmagent accompanied by tumbling in a 
rotating pan. Other standard manufacturing procedures are described in 
Modern Plastics Encyclopedia, Vol. 46, pages 62 to 70, 1969; and in 
Pharmaceutical Sciences, by Remington, 14th Ed., pages 1626 to 1678, 1970, 
published by Mack Publishing Company, Easton, Penna. 
Generally the films can be separately or integrally fabricated and will 
have a thickness of about 2 to 6 mils. The film can be formed with or 
without a film expansion agent and will have a presently preferred 
thickness of about 3.5 to 5.5 mils. The semipermeable walls will have a 
thickness of 5 to 15 mils, with a presently preferred thickness of about 7 
to 12 mils. Of course, thinner and thicker films and walls for use with 
numerous agents and osmagents are within the scope of the invention. 
Exemplary solvents suitable for manufacturing the wall, or the film include 
inert inorganic and organic solvents that do not adversely harm the wall 
forming materials, the film forming materials, and the final system. 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 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, ethylene glycol monoethyl acetate, methylene dichloride, ethylene 
dichloride, propylene dichloride, carbon tetrachloride, nitroethane, 
nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, 
cyclohexane, cyclo-octane, benzene, toluene, naphtha, 1,4-dioxane, 
tetrahydrofuran, diglyme, 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. 
DESCRIPTION OF EXAMPLES OF THE INVENTION 
The following examples are merely illustrative of the present invention and 
they should not be considered as limiting the scope of the invention in 
any way, as these examples and other equivalents thereof will become 
apparent to those versed in the art in the light of the present 
disclosure, the drawings and the accompanying claims. 
EXAMPLE 1 
An osmotic delivery device for the controlled and continuous release of a 
beneficial agent to an environment of use is constructed as follows: 
first, an osmagent compartment is formed by pressing and thinly 
encapsulating a given amount of an osmagent with a film consisting of a 
semipermeable material containing a film expansion agent in an air 
suspension machine. Next, an agent compartment is formed by compressing a 
water soluble agent that exhibits an osmotic pressure gradient across a 
wall into a shape corresponding to the shape of the osmagent compartment. 
Then, a thin layer of a flexible adhesive is applied to one surface of the 
osmagent compartment and the agent compartment juxtapositioned thereto. 
Next, the two compartments are surrounded with a wall of a semipermeable, 
polymeric wall forming material. Finally, a passageway is drilled through 
the wall to the agent compartment to form the osmotic system. 
The system of this example is illustrated in FIG. 1B, and it releases agent 
at a zero order rate of release over a prolonged period of time. In FIG. 
1B, the agent compartment is identified as 13, hereafter referred to as 
the D compartment, the osmagent compartment is identified as 14, hereafter 
referred to as the O compartment, with delivery from system 10, when 
placed in an aqueous environment, governed by the following relations. In 
operation, aqueous fluid is imbibed into the D compartment at a volume 
rate given by Relation 1: 
EQU F = [dV/dt].sub.D (1) 
with agent release from this compartment at a mass rate given by Relation 
2: 
EQU [dm/dt] = F.multidot.C (2) 
wherein C is the concentration of agent in solution. Fluid is imbibed into 
O compartment at a volume rate (dV/dt).sub.O equal to the volume change of 
O compartment (dV.sub.O /dt = O) pushing an equal volume of agent solution 
(-dV.sub.D /dt) as expressed by Relation 3 as follows: 
EQU [dV/dt].sub.O = dV.sub.O/ dt = Q = -dV.sub.D /dt (3) 
adding a simultaneous contribution to the delivery rate as expressed by 
Relation 4: 
EQU [dm/dt].sub.O = Q.multidot.C (4) 
with the total delivery rate from the system obtained from Relation 2 and 4 
as given by Relation 5: 
EQU dm/dt = (F + Q).multidot.C (5) 
the system is advantageously constructed for agents delivering low 
fractions of their agent content at zero order from the osmotic system. 
This invention programs D compartment to formulate the agent solution at a 
constant concentration, S,with the O compartment serving as the driving 
mechanism to deliver agent at a constant rate throughout the lifetime of 
the system. In a two compartment system, both compartments are driven from 
the same external reference solution, and a zero order rate can be 
maintained for a Q sufficiently large to displace all the saturated agent 
solution. Throughout this example, the expandable film is deemed 
impermeable to an agent or osmagent which is correct for a semipermeable 
film separating isotonic solutions. 
Relation 6 describes the minimum mass of osmagent M.sub.O necessary for the 
O compartment to exert a constant force. V.sub.O and V.sub.d are 
respectively the initial osmagent and drug compartment volumes: 
EQU [M.sub.O ].sbsb.min = S.sub.O [V.sub.O + V.sub.D ] (6) 
the system also can be programmed with constant osmotic compartments, O 
compartments, applying a force, or pushing against a D compartment at 
different rates. An important application exists when an O compartment 
exerts a force, or drives, at its maximum value Q.sub.max equal to the 
rate at which agent solution is formulated in D compartment. The release 
rate for the application Q = Q.sub.max achieves its maximum value 
(dm/dt).sub.M for a given agent compartment, D, and is constant throughout 
the total lifetime of the system. The volume rate into D compartment is a 
constant F.sub.S when saturated agent solution is contained in D 
compartment with an osmotic pressure .pi..sub.DS which conditions are 
expressed in Relation 7: 
EQU F.sub.S = k.sub.D .pi..sub.DS .multidot.(A.sub. D/ h.sub.D)(7) 
wherein A.sub.D, h.sub.D, and k.sub.D are respectively the wall area, 
thickness and water permeability of the D compartment. The maximum zero 
order rate of release is then obtained from Relation 8 in which S is the 
agent solubility: 
EQU [dm/dt].sub.Mz = F.sub.S + Q.sub.M ].multidot. S (8) 
expressed as mass per volume of solution, Q.sub.M is equal to the volume of 
agent dissolved in the agent compartment per unit time (dV.sub.C /dt) 
which is related to the agent dissolution rate dm.sub.C /dt as set forth 
in Relation 9 wherein .rho. is the agent's density: 
##EQU1## 
Since a mass of agent, dm.sub.C, dissolves in a volume, dV.sub.W of 
aqueous fluid, dm.sub.C /dV.sub.W in Relation 10 expresses the solubility 
of the agent per unit volume of aqueous fluid, S.sub.W, which is related 
to S by Relation 11 and dV.sub.W /dt is equal to the influx, F.sub.S, into 
D compartment at saturation. This latter result is expressed in Relation 
12. Relations 10, 11 and 12 are as follows: 
##EQU2## 
Substituting Relation 12 into Relation 8, the maximum zero order rate of 
release Z.sub.M is then expressed by Relation 13 or Relation 14 as 
follows: 
##EQU3## 
EQU Z.sub.M = .rho..multidot.Q.sub.M (14) 
in a visual comparison of Relation 9 and Relation 14, it is mathematically 
evident that (dm/dt).sub.M,z as given by Relation 14 is equal to the rate 
of dissolution of agent in the agent compartment as produced by influx 
F.sub.S. Alternatively, Relation 14 can be considered as a mass delivery 
rate produced by a volume flux O.sub.M displacing a mass of agent with 
density .rho.. The zero order time, t.sub.z, is the time necessary to 
deliver the total agent content, M.sub.D,t, as expressed in Relation 15: 
##EQU4## 
For the application where Q &lt; Q.sub.max, the force or pushing rate exerted 
by O compartment is constant but smaller than its maximum value, and under 
these conditions, agent will be dispensed at zero order for a time, 
t.sub.z, followed by a declining delivery rate portion. The zero rate is 
given by Relation 5 expressed as Relation 16: 
##EQU5## 
The zero order rate, Z, can be calculated as a fraction of the maximum 
zero order rate Z.sub.M from Relation 14 and Relation 16 and expressed as 
Relation 17 as follows: 
##EQU6## 
with F.sub.S /Q.sub.M obtained from Relation 12 such that Relation 18 and 
Relation 19 hold as follows: 
##EQU7## 
and Z/Z.sub.M is a linear decreasing function of S/.rho. with slope (1 - 
Q/Q.sub.M). 
The time the system delivers agent at zero order rate is the time required 
to deliver the mass of agent M.sub.Z which is smaller than the total mass 
M.sub.D,t as expressed by Relation 20: 
##EQU8## 
with the mass of agent delivered at zero order being the total mass minus 
the mass not delivered at zero order, or the mass dissolved in the agent 
compartment D at time t.sub.Z according to Relation 21 and Relation 22: 
EQU M.sub.Z = M.sub.D,t - M.sub.NZ (21) 
EQU m.sub.z = m.sub.d,t - SV.sub.D (t.sub.Z) (22) 
with 
EQU V.sub.D (t.sub.Z) = V.sub.DO - Qt.sub.Z (23) 
when V.sub.DO is the original agent volume. From Relation 20 and Relation 
22, M.sub.Z can be eliminated with V.sub.D (t.sub.Z) substituted from 
Relation 23 to yield Relation 24: 
##EQU9## 
Relation 16 and Relation 24 result in Relation 25 in which t.sub.Z is 
expressed independent of Q: 
##EQU10## 
The result states that all osmotic systems constructed with two 
compartments containing the same agent with the same imbibition rate 
F.sub.S take substantially identical times for substantially all the agent 
in D compartment to dissolve; and, the effect or programming different Q's 
will be reflected in the magnitude of the zero order rate of release and 
the amount of agent delivered at zero time. The fraction of agent not 
delivered by the system at a zero order rate of release is given by 
Relation 26 wherein M.sub.NZ is the mass of agent not delivered at a zero 
order rate of release: 
##EQU11## 
and by substituting Relation 23 into Relation 26, the following Relation 
27 and 28 obtained: 
##EQU12## 
and substituting Q.sub.M from Relation 12, Relation 29 is obtained: 
##EQU13## 
which means that when Q = Q.sub.M no non-zero order delivery occurs, and 
when Q = Q, the fraction of agent not delivered from compartment D at a 
zero order rate of release is equal to S/.rho.. The amount of agent 
delivered at a zero order rate of release is then given by Relation 30: 
##EQU14## 
which can be expressed in simplified Relation 31, with Relation 31 
identical to Relation 18 to give Relation 32: 
##EQU15## 
The delivery rate after all the solid agent present in compartment D has 
dissolved in fluid imbibed into the compartment will decline over time 
with the rate of delivery given by Equation 5 with C(t) determined below. 
The mass of agent dissolved in compartment D is expressed by Relation 33 
as follows: 
EQU M.sub.D (t) = C(t) .multidot. V.sub.D(t) (33) 
such that Relation 34 holds: 
##EQU16## 
since 
EQU V.sub.D + V.sub.O = V.sub.total (35) 
and Q is expressed by Relation 36: 
##EQU17## 
and by combining Relation 34 and Relation 36 into Relation 5, Relation 37 
is derived as follows: 
##EQU18## 
and by adopting the notation given in Relation 1: 
EQU F = (F.sub.S /S) .multidot. C (38) 
in which F.sub.S is the volume uptake of the agent compartment D, when 
containing a saturated solution such that Relation 37 and Relation 38 
results in Relation 39: 
##EQU19## 
which can be integrated from t.sub.Z to t as in Relation 40 when the 
concentration changes from S to C: 
##EQU20## 
where V.sub.D (t) is obtained by integrating Relation 36 to yield 
Relations 41 and 42 as follows: 
##EQU21## 
with the compression of the agent compartment D, continuing until a final 
time t.sub.f when F.sub.D (t.sub.f) = 0 which holds in Relation 43 as 
follows: 
##EQU22## 
Substituting Relation 42 into Relation 40 and integrating the combined 
relations, Relation 44 is obtained and simplified as Relation 45: 
##EQU23## 
from which C(t), as mentioned supra is calculated according to Relation 
46: 
##EQU24## 
with Relation 23 substituted in Relation 46 to give Relation 47 
alternatively written as Relation 48: 
##EQU25## 
The non-zero order delivery rate is then obtained from Relations 5, 38 and 
48 and given by Relations 49 and 50 as follows 
##EQU26## 
This delivery rate profile expressed in Relation 50 continues until a time 
t.sub.f = V.sub.DO /Q given by Relation 43 supra, with V.sub.D (t) given 
by Relation 51 and similarly Relation 52: 
EQU V.sub.D (t) = V.sub.DO - Qt (51) 
EQU V.sub.D (t.sub.Z) = V.sub.DO - Qt.sub.z (52) 
Sustituting Relations 51 and 52 into Relation 50 and using the definition 
of t.sub.f of Relation 43, it mathematically follows for Relation 53 that: 
##EQU27## 
Relation 53 can be further normalized by substituting t.sub.Z and t.sub.f 
from Relations 25 and 43 and Z.sub.M from Relation 14 to give Relation 54 
as follows: 
##EQU28## 
which can be expressed in units of t.sub.Z as shown in Relation 55: 
##EQU29## 
which above presentation demonstrates that the volume released from the 
system per unit time expressed as (dm/dt), is related to the volume of 
fluid imbibed into the agent compartment D, in unit time expressed as 
(dV/dt).sub.D, and to the volume of fluid imbibed into the osmagent 
compartment O, in unit time expressed as (dV/dt).sub.O, which relations 
are illustrated in FIGS. 6, 7 and 8. 
EXAMPLE 2 
The procedure employed in this example uses the relations of Example 1. The 
osmotic system suitable for the purpose of this example is designed and 
structured as described in FIGS. 1A through 1F. The osmotic system of the 
example is defined by S, .rho., Q, F.sub.S, M.sub.D,t when Relation 6 is 
satisfied, and for these parameters the osmotic system performance is 
described in terms of normalized quantities as follows: 
##EQU30## 
The maximum zero order rate Z.sub.M is Z.sub.M = .rho..multidot.Q.sub.M ; 
and Q.sub.M /F.sub.S is equal to (S/.rho.)/(1 - S/.rho.). The zero order 
rate Z/Z.sub.M is a linearly decreasing function of S/.rho. with slope (1 
- Q/Q.sub.M) as defined by Relation 19: 
##EQU31## 
with zero order time t.sub.Z defined by Relation 25: 
##EQU32## 
The fraction of agent delivered at zero order M.sub.Z /M.sub.Dt also is a 
linearly decreasing function of S/.rho. and it is identical to Relation 19 
and defined by Relation 30: 
##EQU33## 
The non-zero order delivery rate is given by Relation 54 or by Relation 55 
as a function of time in units of t.sub.Z. 
According to the example, a dual compartment osmotic system comprising an 
agent compartment D, and an osmagent compartment 0, or driving compartment 
is designed and structured to serve the agent compartment. When the 
imbibition flux of the agent compartment is designed at F.sub.S for any 
agent characterized by S and .rho., then the maximum driving rate Q.sub.M 
for the osmagent compartment is given by Relation 12 as plotted in FIG. 6. 
When the osmagent compartment is designed with inbibition flux Q.sub.M, 
the osmotic system delivery profile will be substantially perfect zero 
order at all times at delivery rate Z.sub.M for a time t.sub.Z as shown by 
the square box in FIG. 7, wherein curve A represents Q/Q.sub.M - 0.5, with 
S/.rho. = 0.3, and curve B represents Q/Q.sub.M = 0.8, with S/.rho. = 
0.75. The quantity Z.sub.M is given by Relations 12 and 14 and the 
quantity t.sub.Z is given by Relation 25. 
For this system, when the imbibition rate of the osmotic compartment is Q 
and smaller than Q.sub.M, the zero order time will still be t.sub.Z 
independent of Q. The zero order rate of release Z in this case will be a 
fraction of Z.sub.M as given by Relation 19. Also, the mass of agent 
delivered at zero order M.sub.Z will be an identical fraction of the total 
agent mass delivered according to Relation 30 as shown in FIG. 8. The 
design of an osmotic system according to this example will only be 
necessary for agents with an S/.rho.&gt;0.2. With a dual osmotic system, it 
is necessary that M.sub.Z /M.sub.Dt .gtoreq.0.8 to obtain an optimum 
dosage form index or minimum plasma concentration fluctuation. This 
delivery parameter can be programmed with the dual compartment system and 
it is the area in FIG. 8 in the right hand upper quadrant indicated by 
dashed vertical lines parallel to the ordinate at 0.2 on the abscissa, at 
0.8 on ordinate, and with an upper limit of 1.0. This area contains the 
values of Q/Q.sub.M which can be programmed as indicated by S/.rho. 
values. The fractional amount of agent which is not delivered during the 
time t.sub.Z because Q &lt; Q.sub.M, is delivered in a non-zero order manner. 
Two additional examples are considered for which 85% of the agent is 
delivered at zero order Z/Z.sub.M = 0.85 are plotted in FIG. 7, these are 
identified as curves A and B. For A, when S/.rho. = 0.3 then Q/Q.sub.M = 
0.5 and the zero order rate of release is then Z = 0.85 Z.sub.M. The 
non-zero order rate of release is calculated from Relation 55 with Q.sub.M 
/F.sub.S = 0.0428 as read from FIG. 6. Thus, for these conditions the 
calculations are as follows: 
##EQU34## 
with the final time t.sub.f = Q.sub.M /Q.multidot. t.sub.Z = 
2.multidot.t.sub.Z, and the non-zero order rate of release for this system 
given according to Relation 55 as follows: 
##EQU35## 
with the numerical values obtained listed in Table I and plotted in FIG. 7 
as curve A. In Table I, t/t.sub.Z is the time the osmotic system delivers 
at zero order and 1/Z(dm/dt) is the non-zero order rate of release of 
agent delivered from the osmotic system given as a fraction of the zero 
order rate of release of agent delivered from the osmotic system. 
TABLE I 
______________________________________ 
t/t.sub.Z 1/Z(dm/dt) 
______________________________________ 
1.00 0.850 
1.05 0.577 
1.10 0.414 
1.25 0.187 
1.50 0.07 
1.75 0.03 
______________________________________ 
For B, Z/Z.sub.M = 0.85, S/.rho. = 0.75, and Q/Q.sub.M = 0.8 as seen in 
FIG. 8. For these conditions additional characteric numbers are as 
follows: 
##EQU36## 
with the numerical values obtained listed in Table II and plotted in FIG. 
7 as curve B. The expressions t/t.sub.Z and 1/Z(dm/dt) in Table II are as 
defined for Table I: 
TABLE II 
______________________________________ 
t/t.sub.Z 
1/Z(dm/dt) 
______________________________________ 
1.00 0.85 
1.10 0.66 
1.20 0.45 
1.23 0.35 
1.24 0.30 
1.25 0.20 
______________________________________ 
In A and B the zero order rate of release is identical at 0.85 Z.sub.M. The 
non-zero order rate for each case has a 
##EQU37## 
different time dependency but the mass of drug not delivered at zero order 
is M.sub.NZ as given by the integral for each case. For A where the first 
term in Relation 55 is dominant, the curve is concaved upward, and for B 
where the second term is dominant, the curve is convexed upward. Thus, 
since the osmotic systems are designed with Z/Z.sub.M &gt; 0.8, the time 
dependency of the negligible tail is of little consequence. 
EXAMPLE 3 
An osmotic therapeutic system manufactured in the form of an oral, osmotic 
device for delivering the antiarrhythmic and antifibrillatory drug 
procainamide hydrochloride to the gastointestinal tract was manufactured 
as follows: first, 225 mg of procainamide hydrochloride was pressed into a 
solid mass in a commercially available Manesty tableting machine to a 
Stoke's hardness of 8 kg. Next, the solid was coated in a standard air 
suspension machine with a semipermeable polymeric expandable film formed 
from a 5% solution consisting of cellulose acetate having an acetyl 
content of 32%. The solution was made by dissolving 155 g of cellulose 
acetate in a solvent consisting of 3300 ml of acetone and 330 ml of water. 
The acetone and water had a 88.5 to 11.5 weight to weight basis. The 
freshly formed film had a thickness of 5 mils. 
Next, 350 mg of the osmagent sodium chloride was pressed in the Manesty 
machine to a Stoke's hardness of 8 kg. The pressed sodium chloride had a 
shape identical to the shape of the pressed procainamide hydrochloride. 
Then, a small drop of liquid cellulose acetate was spread onto one surface 
of the pressed sodium chloride and this surface was placed against a 
corresponding surface of the film coated procainamide hydrochloride. The 
two united masses were then coated in the air suspension machine with a 
wall of semipermeable cellulose acetate to a thickness of 10.0 mils. The 
wall was formed using the polymeric solution prepared immediately above. 
Finally, an osmotic passageway having a diameter of 10 mils was drilled 
through one wall facing the procainamide hydrochloride for delivering it 
from the system. 
The procainamide hydrochloride used in this system had a S/.rho. value of 
0.8. For this system containing 225 mg of procainamide hydrochloride the 
minimum amount of sodium chloride required for delivering the procainamide 
hydrochloride was obtained from Relation 6 wherein S.sub.D is the 
solubility of sodium chloride, M.sub.D is the amount of procainamide 
hydrochloride, .rho..sub.D is the density of procainamide hydrochloride, 
and .rho..sub.O is the density of NaCl. 
##EQU38## 
For the system just manufactured Q &lt; Q.sub.M since F/S &gt; .rho./S=1, where 
k.pi..sub.D is the water transmission rate into the agent compartment, 
k.pi..sub.O is the water transmission rate into the osmagent compartment: 
##EQU39## 
wherein the value obtained 0.47 &gt; 0.25 indicates that the system delivery 
rate is functioning at a level less than its maximum rate of release as 
seen in FIG. 9 where the maximum zero order rate is Z.sub.M. Further, from 
Relation 16: 
EQU Z =(F.sub.S = Q) .multidot. S 
EQU = ([k.pi.].sub.D A/h.sub.D + [k.pi.].sub.O A/h.sub.O) .multidot. S 
EQU = (0.0185 + 0.0396) .multidot. 800 
EQU = 46.5 mg/hr, 
which is the system's zero order rate of release which is indicated in FIG. 
9 as Z; also, from Relation 13: 
##EQU40## 
which is the maximum delivery rate Z.sub.M as seen in FIG. 9 along the 
ordinate, and from Relation 25: 
EQU t.sub.Z = M.sub.t /Z.sub.M 
EQU = (225)/74 
EQU = 3.0 hr. 
which is the time the system theoretically delivers the maximum amount at a 
zero order rate of release; and from Relation 43: 
##EQU41## 
which is the time all the agent is expected to be delivered from the 
system; and wherein the non-zero order rate of release is as follows: 
##EQU42## 
wherein dm/dt is plotted in FIG. 9 as the non-zero order rate of release 
indicated by the dashed line. 
In FIG. 9 the actual amount of procainamide hydrochloride released from the 
system was measured and plotted against the calculated amount released 
over a prolonged period of time. The line with the circles represents the 
actual amount released and the dashed lines represents the calculated 
release. The system actually released 70% of its procainamide 
hydrochloride against an expected release of 62%. 
EXAMPLE 4 
An osmotic, therapeutic system was manufactured in the form of an oral, 
osmotic device by following the procedure of Example 3, with all 
conditions and procedures as described, except the film had a thickness of 
7.5 mils and the wall has a thickness of 7.5 mils. For this system F.sub.S 
/Q &gt; .rho./S - 1 or 0.50 &gt; 0.25. Repeating the calculations of Example 3, 
the following values are obtained: Z = 35.2 mg/hr; Z.sub.M = 58.8 mg/hr; 
t.sub.Z = 3.8 hrs.; and t.sub.f = 7.7 hrs. The interpretation of Z, 
Z.sub.M, t.sub.Z and t.sub.F is as in FIG. 3. The non-zero order rate of 
release is given by the following: 
##EQU43## 
wherein dm/dt is plotted in FIG. 10 as the non-zero order rate of release 
indicated by the dashed line. 
In FIG. 10, the actual amount of procainamide hydrochloride released from 
the system of Example 4 was measured and plotted against the calculated 
amount released over a prolonged period of time. The line with the circles 
represents the actual amount released, and the dashed lines represent the 
calculated release. The system actually released 62% of its procainamide 
hydrochloride at constant rate and it had a calculated percentage of 59%. 
EXAMPLE 5 
The procedures of Examples 3 and 4 are repreated in this example with all 
conditions as previously described except that the agent in the agent 
compartment is replaced with a member selected from the group consisting 
of hypnotics, sedatives, psychic energizers, tranquilizers, 
anticonvulsants, muscle relaxants, antiparkinson agents analgesics, 
anti-inflammatory, anesthetics, muscle contractants, anti-microbials, 
antimalarials, hormones, sympathomimetics, diuretics, hypoglycemics, and 
nutritional agents. 
EXAMPLE 6 
The procedures of Examples 3, 4 and 5 are repeated in this example, with 
all conditions as described except that the agent in the agent compartment 
is replaced with a member selected from the group consisting of 
prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, potassium 
chloride, mecamylamine hydrochloride, amphetamine sulfate, benzphetamine 
hydrochloride, isoproternol sulfate, methamphetamine hydrochloride, 
phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, 
atropine sulfate, methscopolamine bromide, isopropamide iodide, 
tridihexethyl chloride, phenformin hydrochloride, and methylpehnidate 
hydrochloride. 
EXAMPLE 7 
The procedures of Example 3 and 4 are repeated in this example with all 
conditions as previously described except that the system is designed as 
an ocular, osmotic therapeutic system and the agent compartment contains 
an ophthalmic drug that is a member selected from the group consisting of 
idoxuridine, phenylephrine, pilocarpine hydrochloride, eserine, carbachol, 
phospholine iodine, demecarium bromide, cyclopentolate, homatropine, 
scopolamine and epinephrine. 
EXAMPLE 8 
In this example, an oral osmotic therapeutic system was manufactured 
according to the procedures of Examples 3 and 4. The procainamide 
hydrochloride of the example was coated with a 3.0 mil thick semipermeable 
polymeric expandable film formed from a 5% solution consisting of 70% 
cellulose acetate having an acetyl content of 38.3%, and 30%, and 30% 
polyethylene glycol having a molecular weight of 400 dissolved in a 80 to 
20 parts by weight of methylene chloride methanol solvent, and then bonded 
to a press mass of osmagent ammonium chloride. The two components were 
finally coated with the cellulose acetate solution of Example 3 to form an 
exterior wall having a thickness of 3.6 mils. The theoretical rate of 
release and the actual rate of release for this system are presented in 
FIGS. 11A and 11B. In the figures, the dashed lines represent the 
theoretical and the line with the circles represent the actual rate of 
release. The system had a measured rate of release of 17 mg per hour for 
11 hours as released through a passageway having a diameter of 8.7 mils. 
This system released 80% of the agent at a zero order rate of release. 
EXAMPLE 9 
The procedure of Example 8 is followed in this example with the 
manufacturing steps as described. In this example, the osmagent ammonium 
chloride is pressed and coated with the expandable film forming solution 
consisting of 70% cellulose acetate having an acetyl content of 38.3% and 
30% polyethylene glycol 400 as prepared in Example 8. The agent of the 
system is pressed into a correspondingly shaped configuration with the 
agent selected from the group of agents having limited solubility that can 
be delivered by the system including diphenidol, meclizine hydrochloride, 
prochlorperazine maleate, thiethylperpazine maleate, anisindione, 
dipenadione, erythrityl tetranitrate, digoxin, isofurophate, reserpine, 
acetazolamide, methazolamide, bendroflumethrazide, allopurinol and 
aspirin. The insoluble agent is admixed with an equal part of sorbitol 
containing methyl cellulose as a binder and suspending agent. The two 
components are adhesively bound and a wall of cellulose acetate having an 
acetyl content of 32% is applied as described in Example 8. The passageway 
communicating with the exterior of the system and the agent compartment 
has a diameter of 8.7 mils. 
EXAMPLE 10 
The procedure of Example 8 was followed in this example with all conditions 
as described except the osmagent in this example was sorbitol. The 
theoretical rate of release and the actual rate of release for this system 
are presented in FIGS. 12A and 13B. In the figures, the dashed lines 
represent the theoretical and the lines with the circles represent the 
actual rate of release. The system had a measured rate of release of 17 mg 
per hour for 12 hours. The passageway had a diameter of 8.7 mils. This 
system released 75 to 85% of the agent at a zero order rate of release. 
EXAMPLE 11 
The procedure of Example 9 is repeated in this example and all 
manufacturing conditions are as described, except the osmagent is a 
mixture of ammonium chloride and sodium chloride. 
EXAMPLES 12 to 14 
Three dual compartment osmotic devices were prepared according to the 
procedures of Examples 3 and 8. The agent compartment in the three devices 
contained procainamide hydrochloride and the osmagent compartment 
contained ammonium chloride. The film surrounding the osmagent was 5 mils 
thick and it consisted of cellulose acetate having an acetyl content of 
36.4% produced by blending cellulose acetate having an acetyl content of 
32% with cellulose acetate having an acetyl content of 39.8% in acetone 
and water. The two compartments were attached with a water soluble paste. 
The wall surrounding the compartments consisted of cellulose acetate 
having an acetyl content of 34.5%. The release parameters for the three 
systems are listed in Table III. 
TABLE III 
______________________________________ 
Wall % Delivered 
Thickness Z t.sub.Z 
t.sub.T 
at Flux 
Eg. Mils (mg/hr) (hr) (hr) Zero Order 
Ratio 
______________________________________ 
12 4 50 4.3 4.3 100 0.19 
13 6 43 5.0 5.0 100 0.25 
14 8 33 5.8 7.0 89 0.29 
______________________________________ 
In Table III, Eg. is example, Z is the zero order rate of agent release, 
t.sub.Z is the time in hours the system delivered at zero order rate of 
release, t.sub.T is the total time the system delivered agent, and Flux 
Ratio is F.sub.S /Q. The systems contained 215 mg of procainamide 
hydrochloride and 325 mg of ammonium chloride. The passageways in the 
systems had a diameter of 10 mils. The actual delivery of agent from these 
systems is plotted in FIG. 13. In FIG. 13, the line with the circles is 
Example 12, the line with the squares is Example 13 and the line with the 
triangles is Example 14. 
The novel osmotic systems of this invention use means for the obtainment of 
precise release rates in the environment of use while simultaneously 
maintaining the integrity and character of the system. While there has 
been described and pointed out features of the invention as applied to 
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 of the invention.