Therapeutic device for osmotically dosing at controlled rate

An osmotic device is disclosed for delivering an active agent. The device comprises a wall surrounding a compartment with a passageway through the wall for releasing the agent. The wall comprises a material permeable to an external fluid and substantially impermeable to agent and at least one additional material independently selected from materials that impart stability to the wall, enhance the permeability of the wall to fluids, or aid in forming the wall. The compartment contains an agent that exhibits an osmotic pressure gradient across the wall against an external fluid, or the agent is mixed with an osmotically effective compound that exhibits an osmotic pressure gradient against the fluid. Agent is released from the device by fluid being imbided through the wall into the compartment at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall, thereby producing a solution containing agent that is released through the passageway at a controlled rate over time.

FIELD OF THE INVENTION 
This invention pertains to an osmotic device. More particularly, the 
invention relates to an osmotic device having a wall formed of a plurality 
of semipermeable wall forming materials for delivering an active agent at 
a controlled and continuous rate over a prolonged period of time to an 
environment of use. 
BACKGROUND OF THE INVENTION 
Osmotic devices for delivering a beneficial agent to an environment of use 
are known to the prior art in U.S. Pat. Nos. 3,845,770 and 3,916,899. The 
devices disclosed in these patents are made with a wall formed of a 
material that is permeable to an external fluid and substantially 
impermeable to agent. The wall surrounds a compartment that contains an 
agent and there is a passageway through the wall for dispensing the agent. 
These devices are remarkably 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 wall 
against the fluid, and for delivering an agent that has limited solubility 
in the fluid and is admixed with an osmotically effective compound soluble 
in the fluid that exhibits an osmotic pressure gradient across the wall 
against the fluid. The devices release agent by fluid being continuously 
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 soluble compound 
containing agent which solution in either operation is dispensed from the 
device. While the above devices represent a significant and pioneer 
advancement in the art and they are useful for dispensing numerous agents, 
there is an occasional instance where the agent may have an unwanted 
effect on the device. For example, a wall formed of cellulose acetate 
having a low acetyl content in the presence of certain agents can slowly 
lose its integrity over a prolonged period of time thereby slowly changing 
the rate of imbibition and concomitantly the rate of agent release from 
the device over a correspondingly prolonged period of time. 
OBJECTS OF THE INVENTION 
Accordingly, it is an immediate object of this invention to provide an 
improved osmotic device for the controlled and continuous dispensing of an 
active agent over a prolonged period of time which device overcomes the 
problems known to the prior art. 
Another object of the invention is to provide an osmotic device that 
maintains its physical and chemical integrity during the controlled and 
continuous dispensing of an agent over a prolonged period of time. 
Yet another object of the invention is to provide an osmotic device 
designed with a minimum number of parts and having at least one wall 
formed of a plurality of wall forming materials that makes the wall 
substantially inert towards agents and solutions thereof. 
Another object of the invention is to provide an osmotic device for 
dispensing drugs that because of their inherent properties are difficult 
to dispense, and which drugs can be dispensed with the device of this 
invention at a controlled and continuous rate to perform their intended 
therapeutic effects. 
Still a further object of the invention is to provide an osmotic dispensing 
system that can administer a complete pharmaceutical regimen to a human 
for a particular time period, the use of which requires intervention only 
for initiation and possibly termination of the regimen. 
Still a further object of the invention is to provide osmotic devices 
having a wide spectrum of semipermeable walls in which wall properties 
such as the fluid flow-through rate and agent resistance may be controlled 
and varied to the particular application. 
Still another object of the invention is to provide an improved osmotic 
device for delivering drugs that are difficult to deliver and drugs that 
require multiple doses, and which device can deliver the drugs over a 
prolonged period of time and also eliminate the necessity for taking 
multiple doses of drug. 
Yet still another object of the invention is to provide an osmotic device 
having a wall that has a high flux rate to fluids, a high degree of 
exclusion towards agents and improved resistance to hydrolipis in the 
presence of agents over a wide pH range. 
Yet still another object is to provide an osmotic device that can deliver 
all kinds of drugs and has an economic advantage for the user by keeping 
to a minimum the number of doses to be administered and reducing missed 
doses because of forgetfulness. 
Other objects, features and advantages of the invention will be more 
apparent to those skilled in the art from the following specification, 
taken in conjunction with the drawings and the accompanying claims. 
SUMMARY OF THE INVENTION 
This invention concerns an osmotic device useful for dispensing an active 
agent to an environment of use. The device is comprised of a wall 
surrounding a compartment and has a passageway communicating with the 
compartment and the exterior of the device. The compartment contains 
either an agent that exhibits an osmotic pressure gradient across the wall 
against an external fluid, or it contains a mixture of an agent and an 
osmotically effective compound that exhibits an osmotic pressure gradient 
across the wall against the fluid. The wall is comprised of a blend of a 
wall forming material with the wall being permeable to the external fluid, 
substantially impermeable to agent and substantially inert to agent and 
solutions thereof. Agent is dispensed from the device by fluid being 
imbibed through the wall into the compartment to dissolve agent or the 
compound and produce a solution that is released under osmotic pressure 
from the device through the passageway at a controlled and continuous rate 
over a prolonged period of time.

DETAILED DESCRIPTION OF THE DRAWINGS 
Turning now to the drawings in detail, which are examples of various 
osmotic delivery devices of the invention, and which examples are not to 
be considered as limiting, one example of an osmotic device is indicated 
in FIGS. 1A and 1B, considered together, by numeral 10. Device 10 is 
comprised of a body 11 having a wall 12 that surrounds a compartment 13, 
seen in FIG. 1B in opened-section with a portion of wall 12 removed at 14, 
and a passageway 15 in wall 12 that communicates with compartment 13 and 
the exterior of device 10. Compartment 13, as seen in FIG. 1B, in one 
embodiment is a means for containing an agent 16 that is soluble in an 
external fluid and exhibits an osmotic pressure gradient across wall 12 
against the fluid, or compartment 13 can contain a mixture of agents with 
at least one agent exhibiting an osmotic pressure gradient. In another 
embodiment, compartment 13 contains an agent that has limited solubility 
or is substantially insoluble in the external fluid mixed with an 
osmotically effective compound 17 that is soluble in the external fluid 
and exhibits an osmotic pressure gradient across wall 12 against the 
fluid. Compartment 13 also can contain other compounds 17 such as a 
surfactant for wetting the agent and a non-toxic dye for either 
identifying the agent or for making release of agent visible to the eye. 
Wall 12 of device 10 is comprised in whole or in at least a part of a 
composite of at least two wall forming materials blended to form a wall 
that is (a) permeable to the passage of an external fluid, (b) 
substantially impermeable to the passage of agent 16 and other compounds 
17 housed in compartment 13, (c) is substantially inert in the presence of 
agent 16, compound 17 and solutions thereof, and (d) maintains its 
physical and chemical integrity in the environment of use during the 
dispensing of active agent. When wall 12 is formed in part of a 
semipermeable composite, the remainder of 12 is formed of a material that 
is substantially impermeable to fluid and to the passage of agent 16 and 
compound 17 housed in compartment 13. A detailed description of wall 
forming materials, agents and other compounds appears later in the 
specification. 
In operation in the environment of use, device 10 in one embodiment 
releases agent 16 housed 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 continuously dissolve 
agent 16 which is osmotically pumped from device 10 through passageway 15 
at a controlled and continuous rate over a prolonged period of time. 
Device 10, in another embodiment, releases agent 16 that has limited 
solubility in the fluid and is mixed with an osmotically effective 
compound 17 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 gradient across wall 12 to 
continuously dissolve compound 17 to form a solution containing agent 16 
which is pumped from device 10 through passageway 15 at a controlled and 
continuous rate over a prolonged period of time. 
Device 10 of FIGS. 1A and 1B can be made in many embodiments including the 
presently preferred embodiment for oral use, that is, for releasing in the 
gastrointestinal tract either a locally or systemically acting therapeutic 
agent over a prolonged period of time. Oral device 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. 
FIG. 2 represents another device 10 manufactured according to the invention 
and designed for topically administering drug. Device 10 is comprised of a 
semipermeable composite wall 12 surrounding a compartment, not shown, that 
contains an agent or a mixture of agent and an osmotically effective 
compound. Device 10 has two passageways for releasing drug. Passageways 15 
can be of the same or of different sizes so long as the total opened area 
lets device 10 operate as an osmotic device. Device 10 has a pair of 
integral straps optionally either coated with an adhesive for suitably 
mounting device 10 to the surface of an animal, not shown, or straps 18 
can have fastening strips of the Velcro.RTM.-type as disclosed in U.S. 
Pat. No. 3,086,529 on their ends for fastening device 10 around an arm or 
leg for administering drug thereto. It is sometimes preferred to fix 
one-half of each of the Velcro.RTM. strips on device 10 to mate with the 
opposite strip on strap 18. Device 10 operates to release drug topically 
in the same way device 10 of FIGS. 1A and 1B operates to release agent 16 
to the environment of use. 
FIG. 3 illustrates an osmotic device 10 designed for releasing an agent 
within a body opening, the anal canal not shown. Device 10 is shaped like 
a tube and it has a lead end 19, a distant trailing end 22 and a plurality 
of circumferentially spaced ribs 23 extended along the length of device 
10. Ribs 23 at end 22 unite with a downwardly facing shoulder 20 that is 
formed with an annular removable closure 21 for filling device 10. Ribs 23 
serve to grasp the cellular wall of the anal canal and also to increase 
the exposed surface of device 10 for imbibing anal fluid into the device. 
Wall 12 of device 10 is comprised of a semipermeable composite material 
and it surrounds a compartment, not shown, that contains an agent. A 
passageway 15 at end 19 extends through wall 12 for releasing agent from 
the compartment to the exterior of device 10. Device 10 of FIG. 3 releases 
either a locally or systemically acting agent in the anal canal in the 
same way device 10 of FIGS. 1A and 1B releases agent 16 to an environment 
of use. 
FIG. 4 shows an osmotic device 10 within a vaginal tampon 24 that is 
designed for placement in a vagina. Tampon 24 has an elongated, 
cylindrical, precompressed, self-sustaining shape with a rounded lead end 
25 and a slightly curved rear end 26. Tampon 24 is made of cotton wadding 
28 and it is equipped with a manually controlled cord 27 for easily 
removing it from a vagina. Tampon 24 serves as a platform for osmotic 
device 10. Device 10 is structurally identical with device 10 as described 
above and it also operates in a like manner. Device 10 of FIG. 4 in one 
embodiment contains a drug designed for absorption by the vaginal mucosa 
to produce a local or systemic effect. In another embodiment, device 10 
contains an odor reductant that emits an odor counteracting scent for 
fragrance in the vagina. 
Referring to FIG. 5, device 10 is seen in an eye 28 for administering drug 
at an osmotically metered dosage rate. In FIG. 5, eye 28 is comprised of 
an upper eyelid 29 with eyelashes 30 and a lower eyelid 31 with eyelashes 
32. Eye 28 anatomically is comprised of an eyeball 33 covered for the 
greater part by sclera 34 and at its center area by cornea 35. Eyelids 29 
and 31 are lined with an epithelial membrane or palpebral conjunctiva, and 
sclera 34 is lined with a bulbar conjunctiva that covers the exposed 
surfaces of eyeball 33. Cornea 35 is covered with a transparent epithelial 
membrane. The portion of the palpebral conjunctiva which lines upper 
eyelid 30 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 31 and the underlying portion of the bulbar conjunctiva 
defines a lower cul-de-sac. Ocular, osmotic device 10 is designed for 
placement in the upper or lower cul-de-sac. Device 10 is seen in the lower 
cul-de-sac and it is held in place by the natural pressure of lower eyelid 
31. Device 10 contains an ophthalmic drug for osmotic release to eye 28. 
Ocular device 10 can have any geometric shape that fits comfortably in the 
cul-de-sac. Typical shapes include ellipsoid, bean, banana, circular, 
rectangular, doughnut, crescent and half-ring shaped devices. In 
cross-section, the devices 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 device can vary widely with 
the lower limit governed by the amount of drug to be supplied to the eye 
as well as by the smallest sized device that can be placed into the eye. 
The upper limit on the size of the device is governed by the space 
limitation in the eye consistent with comfortable retention in the eye. 
Satisfactory devices generally have a length of 4 to 20 millimeters, a 
width of 1 to 15 millimeters. The ocular device can contain from 0.15 
micrograms to 100 milligrams of drug, or more, and it is made from 
non-erodible and inert materials that are compatible with the eye and its 
environment. 
FIG. 6 diagrammatically illustrates the use of osmotic device 10. In FIG. 
6, there is seen device 10 mounted on the arm 35 of a human for 
administering drug thereto. Device 10 is connected through passageway 15, 
not shown, to one end of a flexible conduit 36 which is connected at its 
other end to a needle 37 for releasing drug to drug receptor 38. Device 10 
is structured and operates as previously described and it administers drug 
at a controlled and continuous rate to receptor 38, the antecubital vein, 
not shown, for a prolonged period of time. 
While FIGS. 1 through 6 are illustrative of various devices that can be 
made according to the invention, it is to be understood these devices are 
not to be construed as limiting, as the devices can take a wide variety of 
shapes, sizes and forms for delivering agent to different environments of 
use. For example, the devices include buccal, implant, artificial gland, 
cervical, intrauterine and ear devices. The devices also can be adapted 
for delivering an active agent in streams, aquariums, fields, factories, 
reservoirs, laboratory facilities, hot houses, transportation means, naval 
means, air and military means, hospitals, veterinary clinics, nursing 
homes, 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 device 10 can be manufactured with an improved wall(s) comprised of 
at least two wall forming materials blended to form a wall that is (a) 
permeable to the passage of an external fluid present in the environment 
of use, (b) substantially impermeable to the passage of agent 16 and other 
compounds 17 housed in compartment 13, (c) is substantially inert in the 
presence of agent 16, compounds 17 and solutions thereof, and (d) 
maintains its physical and chemical integrity in the environment of use 
during the dispensing of agent 16. Wall 12 is comprised of (1) at least 
one wall forming material permeable to the fluid and substantially 
impermeable to agent 16 and other compounds 17 blended with at least one 
or more of the following wall forming materials, (2) a stabilizing 
material that imparts physical and chemical integrity to wall 12, and more 
particularly gives wall 12 inertness towards agent 16, compounds 17, 
solutions thereof, and to compounds present in the environment of use, (3) 
a flux enhancer that promotes the permeability of fluid through wall 12, 
(4) a plasticizer that gives flexibility to the wall, and (5) a dispersant 
useful for blending the materials into an operative integral composite 
wall. The wall's integrity or inertness to agents in the compartment, and 
to fluids and other compounds in the environment of use can, according to 
the mode and manner of the invention, be precisely regulated by selecting 
the ingredients blended into the wall forming the device. The fluid 
permeability of the wall can be regulated in a like manner. The term 
"composite" as used herein means the wall is comprised of a blend of 
materials that act together to form the operative integral wall of the 
device. 
Exemplary materials for forming wall 12 are polymers permeable to fluids 
and substantially impermeable to agents and substantially impermeable to 
other compounds. Polymers that are useful for the purpose identified above 
by (1) generically include wall forming polymers comprised of 
anhydroglucose units. In one embodiment the polymers are cellulose esters 
and ethers having a degree of substitution, D.S., on the anhydroglucose 
unit from greater than 0 up to 3 inclusive. By "degree of substitution", 
as used herein, is meant the average number of hydroxyl groups originally 
present on the anhydroglucose unit replaced by a substituting group. 
Exemplary polymers are represented by Formula 1: 
##STR1## 
wherein R.sub.1, R.sub.2 and R.sub.3 are the same or different and they 
are selected from the group consisting of hydrogen; alkyl; alkenyl; amino; 
alkanoyl; alkanoyl substituted with a member selected from the group 
consisting of alkoxy, halogen, hydroxyl, alkanoyl, carboalkyl, carboalkoxy 
and cyanoalkoxy; aroyl; aroyl substituted with a member selected from the 
group consisting of hydroxyl, carboxyl, carboalkyl and cyano; benzyl; 
carboalkyl; carboxyalkyl; dialkoxyalkyl; dithiocarbonyl; hydroxyalkyl; 
cyanoalkyl; nitro; phenyl; sulfoalkyl; the alkali metal salts thereof; and 
wherein said polymer exhibits a degree of substitution at R.sub.1, 
R.sub.2, and R.sub.3 of greater than 0 up to 3, and n is greater than 5. 
Exemplary of alkyl groups for the purpose of the invention are the straight 
and branched chain type having 1 to 20 carbons, such as methyl, ethyl, 
n-propyl, iso-propyl, n-butyl, sec-butyl, pentyl, neo-pentyl, n-hexyl, 
iso-hexyl, heptyl, 4,4-dimethyl pentyl, 2,2,4-trimethylpentyl, nonyl, 
decyl, 2,5-dimethyl decyl, and the like. By "alkenyl" is meant straight or 
branched chain alkenyl groups of 2 to 20 carbons such as 1-propenyl, 
2-propenyl or allyl, 1-butenyl, 2-butenyl, 1-pentyl, and the corresponding 
positional isomers such as 1-isobutenyl, 2-iso-butenyl, 2sec-butenyl, 
2-methyl-1-butenyl, 2methyl-2pentylnyl, 2,3-dimethyl-3hexenyl, and the 
like. The term "alkoxy" as used herein includes the straight and branched 
chain alkoxy groups having 1 to 20 carbons inclusive; for example, 
methyoxy, ethoxy, propoxy, butoxy, n-pentoxy, n-hexoxy, isopropoxy, 
2-butoxy, isobutoxy, 3-pentoxy, n-octoxy, and the positional isomers 
thereof. 
The term alkanoyl, as used herein, includes alkanoyls of 1 to 20 carbon 
atoms such as formyl, acetyl, propionyl, butyrl, hexanoyl, heptanoyl, 
octanoyl, undecanoyl, lauroyl, palmitoyl, stearoyl, oleoyl, and isomeric 
forms thereof. The term aroyl as used herein includes aroyls of 7 to 15 
carbon atoms such as benzoyl, phenylacetyl, cinnamoyl, naphthoyl, 
p-ethoxybenzoyl, alloxyphenylacetyl, p-nitrobenzoyl, 3-chlorobenzoyl, and 
the like. Exemplary aryls include 6 to 15 carbons such as phenyl, benzyl, 
naphthyl, and the like. Exemplary halogens include fluorine, bromine, and 
chlorine. Representative alkali metal salts include sodium, potassium, 
lithium, and the like. 
Representative materials embraced by Formula 1 include polymeric cellulose 
esters and copolymeric cellulose esters that are unsubstituted and 
substituted, such as mono, di, and tricellulose alkanoylates and 
aroylates. Exemplary polymers include cellulose acetate having a D.S. up 
to 1 and an acetyl content of up to 21%; cellulose diacetate having a D.S. 
of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetate having 
a D.S. of 2 to 3 and an acetyl content of 35 to 44.8%; cellulose 
propionate having a D.S. of 1.8 and a propionyl content of 38.5%; 
cellulose acetate propionate having an acetyl content of 1.5 to 7% and a 
propionyl content of 39 to 42%; cellulose acetate propionate having an 
acetyl content of 2.5 to 3%, an average combined propionyl content of 39.2 
to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate 
having a D.S. of 1.8, an acetyl content of 13 to 15%, %, a butyryl content 
of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 
29.5%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 
4.7%; cellulose triacylates having a D.S. of 2.9 to 3 such as cellulose 
trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose 
trisuccinate, cellulose triheptylate, cellulose tricaprylate, cellulose 
trioctanoate, and cellulose tripropionate, cellulose diesters having a 
lower degree of substitution prepared by the hydrolysis of the 
corresponding triester to yield cellulose diacylates having a D.S. of 2.2 
to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose 
dioctanoate, cellulose dicaprylate, and cellulose dipentanate; and esters 
prepared from acyl anhydrides or acyl acids in an esterification reaction 
to yield esters such as cellulose acetate valerate, cellulose acetate 
succinate, cellulose propionate succinate, cellulose acetate octanoate, 
cellulose valerate palmitate, cellulose acetate palmitate, and cellulose 
acetate heptanoate. 
Additional polymers embraced by Formula 1 include methyl cellulose, ethyl 
methyl cellulose, sulfomethyl cellulose, carboxymethyl cellulose, allyl 
cellulose, amino cellulose, carboxyethyl methylcellulose, benzylcellulose, 
phenylcellulose, ethylcellulose, cyanomethyl cellulose, p-methoxybenzoyl 
cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydroxyhexyl 
cellulose, carboxymethyl hydroxyethyl cellulose, cellulose acetate 
diethylamino acetate, chloroethyl methyl cellulose and the like. 
Generally, the materials useful for forming the wall will have a fluid 
permeability of 10.sup.-5 to 10.sup.-1 (cc.mil/cm.sup.2.hr.atm), expressed 
per atmosphere (atm) of hydrostatic or osmotic pressure difference across 
the membrane at the temperature of use while possessing a high degree of 
impermeability to solute are useful for the purpose of the invention. The 
polymers described above are known to the art in references such as 
Chemical Abstracts, Vol. 51, 10892(c), 12463(f), 1957; Vol. 55, 17002(h), 
1961; and Vol. 66, 12024(m), 12026(p), 1967; U.S. Pat. Nos. 3,721,582 and 
3,732,205, or they can be prepared according to the procedures in 
Encyclopedia of Polymer Science and Technology, Vol. 3, pages 325 to 354, 
1964, published by Interscience Publishers Inc., New York. Criteria that 
can be used for selecting the wall forming material and the stabilizing 
material embraced by Formula 1 and by Formula 2 as illustrated below, are 
presented later in the specification. 
The expressions "stabilizing material" and "wall forming stabilizing 
material" as used herein include polymers that impart integrity to the 
final wall in the presence of drug and in the environment of use, which 
environments includes the gastrointestinal tract. The polymers are in a 
presently preferred embodiment embraced by Formula 2 as follows: 
##STR2## 
wherein R.sub.5, R.sub.6 and R.sub.7 are members selected from the group 
consisting of hydroxyl; nitrate hydroxyalkyl; alkoxy; aryloxy; 
hydroxyalkoxy; hydroxyalkalkoxy; trityloxy; oxalkyleneoxycarboalkyl; with 
at least one of R.sub.5, R.sub.6 and R.sub.7 a member selected from the 
group consisting of aryoloxy, alkanoyloxy, carboxyalkoxy, 
carbamoyloxyalkoxy, carboxyalkoxyacyloxy, carboxy, carboxybenzoyl, 
carboxybenzoyloxy, carboxybenzoyloxyalkoxy, and dialkylaminohydroxyalkoxy; 
the alkali metal salts thereof, and wherein n is greater than 5, usually 
10 to 3.times.10.sup.6, and the polymer exhibits a degree of substitution 
at R.sub.5, R.sub.6 and R.sub.7 of greater than 0 up to 3. 
Exemplary groups representative of R.sub.5, R.sub.6 and R.sub.7 of Formula 
2 are those groups as defined above and the following: hydroxyalkyl such 
as hydroxyalkyl wherein the alkyl has 1 to 20 carbons such as 
hydroxyalkyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and 
the like. The term hydroxyalkoxy as used herein includes straight and 
branched chain alkoxy groups having 1 to 20 carbon atoms substituted with 
a hydroxyl group; for example, hydroxymethoxy, hydroxyethoxy, 
hydroxypropoxy, hydroxybutoxy, hydroxypentoxy, hydroxyhexoxy, 
hydroxyisopropoxy, hydroxyisobutoxy, hydroxyoctoxy, and the like. 
Exemplary alkylene as a linking moiety within a substituent are alkylenes 
of 1 to 10 carbons such as 1,2-ethylene, 1,3-propylene, 1,2-propylene, 
1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene and 
1,10-decylene. Exemplary alkanoyloxy of 1 to 20 carbons and aroyloxy of 7 
to 15 carbons include formyloxy, acetyloxy, propionyloxy, valeryloxy, 
heptanoyloxy, octanoyloxy, undecanoyloxy, lauroyloxy, palmitoyloxy, 
stearoyloxy oleoyloxy, 3-butenoyloxy, benzoyloxy, phenylacetyloxy, 
cinnamoyloxy, naphthoyloxy, p-ethoxybenzyloxy, alloxyphenylacetyloxy, 
furoyloxy, p-nitrobenzoyloxy, chlorophenoxyacetyloxy, and the like. 
The polymers embraced in Formula 2 include polymers having a degree of 
substitution on the anhydroglucose unit greater than from 0 up to 3 
inclusive. The substituents at R.sub.5, R.sub.6 and R.sub.7 can be the 
same, or they can be different groups. The polymers can be polymeric 
cellulose esters or polymeric cellulose ethers. The repeating monomeric 
unit in a polymer can be substituted with like ester groups, with 
different ester groups, with like ether groups, with different ether 
groups and with different mixed ester and ether groups. Typical polymers 
represented by Formula 2 include dimethoxyethylcellulose acetate, 
cellulose acetate carboxymethoxypropionate, cellulose acetate phthalate, 
cellulose butyrate naphthylate, cellulose acetate benzoate, 
methylcellulose acetate, cellulose acetate methoxyacetate, cellulose 
triacetate, cellulose acetate methylcarbamate, cellulose acetate 
ethylcarbamate, hydroxypropyl methylcellulose phthalate, hydroxypropyl 
butylcellulose phthalate, hydroxyethylcellulose, hydroxypropylcellulose, 
hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, ethylhydroxy 
ethylcellulose, hydroxybutyl methylcellulose, benzylcellulose, sodium 
carboxymethylcellulose, sodium carboxymethylhydroxy ethylcellulose, 
carbamoylethylcellulose, carboxyethylcellulose, phenylcellulose, 
benzylhydrylcellulose, tritylcellulose, hexylpropylcellulose, 
carboxylbenzyl cellulose, and 2-carboxylbenzyoyloxy propylcellulose. The 
polymers of Formula 2 are known to the art in references such as U.S. Pat. 
Nos. 3,646,179; 3,718,728; 3,896,108; and 3,892,665; in Chemical 
Abstracts, Vol. 44, 8675(g), 1956; Vol. 50, 11248(e), 1957; Vol. 55, 
10888(a) and 17002(h), 1961. Methods for preparing the cellulose ethers 
are disclosed in Encyclopedia of Polymer Science and Technology, Vol. 3, 
pages 459 to 549, 1964, published by Interscience Publishers, Inc., New 
York. 
In another preferred embodiment the polymers of Formula 2 can be replaced 
with a member selected from the group consisting of acylated 
polysaccharides and acylated starches such as agar-agar acetate, acylated 
alginates, amylose triacetate, beta glucan acetate, beta glucan 
triacetate, acetyl alginate, triacetate of locust bean gum, alkanoyl 
carrageenan, acylated tragacanth, esterified gum karaya, cellulose 
derivatives substituted with an inorganic moiety such as a nitro group, 
hydroxylated ethylene vinylacetate, aromatic nitroen containing polymeric 
materials that exhibit permeability to aqueous fluids and substantially no 
passage to solute, semipermeable membranes made from polymeric epoxides, 
copolymers of alkylene oxides and alkyl glycidyl ethers, polyvinyl 
acetate, cross-linked polyvinyl acetate, polyurethanes, film forming 
materials as disclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132, 
cross-linked derivatives of polyvinyl alcohol, polyvinyl butyrate, 
mixtures of polyvinyl acetate and cellulose esters, ionically associated 
semipermeable polyelectrolytes, polymers formed by the coprecipitation of 
a polycation and a polyanion as described in U.S. Pat. Nos. 3,276,586; 
3,541,005; 3,541,006; 3,546,142; and 3,173,876; for example, polystyrene 
derivatives such as poly(sodium styrene sulfonate) and 
poly(vinylbenzyltrimethyl ammonium chloride); also, semipermeable 
polyesters, polyamides and polyacrylates. These polymers and other 
polymers are known to the art and they are disclosed in Handbook of Common 
Polymers by Scott, J. R., and Roff, W. J., 1971, published by CRC Press, 
Cleveland, Ohio. Usually, from 0.01 to 50 parts, preferably from 0.1 to 30 
parts, of stabilizer are incorporated into 100 parts of shaped wall to 
yield an operable device. 
Suitable wall forming polymers for manufacturing an osmotic device can be 
selected from the above materials according to the criterion disclosed in 
U.S. Pat. No. 3,916,899. This criterion consists in first calculating, for 
a membrane that is to be selected, the permeability to fluid necessary to 
deliver an amount of agent Q.sub.P, in mg, in time t, in hours, from a 
device having a total membrane area A, in cm.sup.2, a membrane thickness 
h, in mils, with the agent having a solubility in the fluid S, in mg/ml 
(solution), and the agent having an osmotic pressure in the device .pi., 
in atm. The value k is expressed in units cm.sup.3 /cm.sup. 2.mil/hr.atm, 
and it is calculated from Equation 1. 
EQU k=h/S A.multidot.Q.sub.p /t.multidot.1/.pi. (1) 
Then, after having calculated the desired membrane permeability k from 
Equation 1, laboratory measurements ae made to identify a wall forming 
material capable of forming a membrane having a permeability k.sub.o 
substantailly equivalent to the calculated permeability k. The 
measurements are carried out by using a standard osmosis cell and 
measuring the rate of fluid flow through a membrane made of wall forming 
material having a known composition and thickness. The flow rate is 
determined by measuring fluid transport from a first chamber containing a 
fluid free of agent through a membrane that separates it from a second 
chamber housing a solution containing a known concentration of agent that 
exhibits an osmotic gradient across the membrane. Sometimes the chamber 
contains an osmotically effective compound which is used as osmotic 
driving agent. The flow measurement is performed by adding to the first 
chamber the fluid and then adding to the second chamber, equipped with a 
stirring bar, the same fluid containing agent, and optionally containing 
the additional osmotic agents. The first chamber is connected through a 
conduit to a reservoir containing a supply of fluid and the second chamber 
is connected to a vertically positioned tube of known diameter and 
calibrated with indicia that indicate the amount of fluid in the tube. In 
operation, fluid flows from the first chamber through the membrane into 
the second chamber by osmosis causing the solution to rise in the tube 
over time, t, to give a volume displacement, .DELTA.V, during a time 
interval, .DELTA.t. The volume, .DELTA.V, is read on the tube calibrated 
in cm.sup.3, and the time interval, .DELTA.t, is measured with a 
stopwatch. The value k.sub.o .pi. in cm.sup.3 .multidot.mil/cm.sup.2 hr 
for the membrane with permeability, k.sub.o, for the agent solution with 
an osmotic pressure, .pi., is calculated from Equation 2, wherein A.sub.o 
is the area of the membrane, in the diffusion cell, and h.sub.o is the 
thickness of this membrane. 
EQU k.sub.o .pi.=.DELTA.V/.DELTA.t.multidot.h.sub.o /A.sub.o (2) 
If the measured value, k.sub.o .pi., approximates the calculated value, 
k.pi., the membrane can be used for manufacturing the osmotic device. 
Other procedures and devices useful for measuring fluid permeability and 
osmotic flow are disclosed in J. App. Poly. Sci., Vol. 9, pages 1341 to 
1362, 1965; and in Yale J. Biol. Med., Vol. 42, pages 139 to 153, 1970. 
Suitable stabilizing materials can be selected from the above materials for 
blending with the wall forming materials by those skilled in the art by 
using the procedures described below. These procedures are the membrane 
weight loss and the osmosis procedure. The procedures use membranes formed 
with stabilizers and formed without stabilizers. The membrane weight loss 
is carried out with membranes that are cast from solution or optionally 
melt pressed. The membranes are solution cast with a Gardner film-casting 
knife on a clean glass plate at room temperature with the solution removed 
by evaporation in an oven at elevated temperatures until the membranes are 
dry. Next, the membranes are removed from the glass and cut into strips 1 
to 10 cm in length, 1 to 10 cm in width and having a thickness of 1 to 10 
mils. Then, after all the strips are cut to have the same area and weight, 
they are placed in a glass container filled with a solution consisting of 
a known concentration of agent formulated with the fluid of the 
environment of use. The temperature of the container is made to correspond 
to the temperature of the environment where an osmotic device formed with 
the membranes will be placed for releasing agents. At regular time 
intervals, strips are taken from the solution, rinsed in distilled water, 
dried in an oven, usually 50.degree. C. for 24 hours, and weighed. The 
weight of a single strip repeatedly introduced into the solution, or the 
weight of many strips consecutively removed at different time intervals, 
is indicated along the ordinate, plotted as a function of time indicated 
along the abscissa, such as t.sub.1, t.sub.2, t.sub.3, etc., as shown in 
FIG. 7. In FIG. 7, line 1 represents the results obtained for a membrane 
that maintains its physical and chemical integrity when exposed to agent 
solution. That is, the membrane does not lose any weight over time and 
demonstrates inertness in the presence of agent solution. In the same 
Figure, line 2 represents a membrane which upon exposure to agent 
solution, demonstrates weight loss and is undesirable for making an 
osmotic device. A stabilizer can be blended into this membrane to enhance 
its inertness and substantially prevent weight loss, thereby making the 
membrane useful for fabricating devices. 
In the osmosis procedure, the rate of fluid flow through a membrane is 
measured and it is performed using an osmosis cell. The purpose of the 
procedure is to ascertain (1) if a given membrane maintains its integrity 
in the presence of fluid and agent, and (2) if a stabilizer added to the 
membrane increases its physical and chemical integrity as seen from flux 
measurements. The procedure is carried out using the cell according to the 
above described procedure with the volume of solution, .DELTA.V, rising in 
the tube attached to chamber 2 measured and plotted as a function of time, 
t. The data obtained for two different membranes are shown in FIG. 8. In 
FIG. 8, line 1 represents a membrane that maintains its integrity in the 
presence of fluid and agent. That is, since the rate of fluid flow is 
substantially constant, the membrane does not undergo any substantial 
change over time, t. Line 2 shows the fluid flux, .DELTA.V/.DELTA.t, 
through a membrane where the rate is continually increasing over time. 
This change indicates the membrane does not maintain its integrity in the 
presence of fluid and agent. For those applications where a change in flux 
is unwanted, a stabilizer can be added to the membrane to enhance its 
inertness. The flux through membranes containing stabilizer is measured as 
just described. 
Using the above techniques, one versed in the art would use the weight loss 
and osmosis procedures for ascertaining if the fluid and agent adversely 
affect the membrane and also for determining if a stabilizer blended into 
the membrane overcomes this effect. The stabilizer can be added in varying 
amounts to obtain an acceptable slope as seen in FIG. 7 and 8, with the 
stabilizer decreasing the slope, not shown, indicating a lessening of 
membrane agent solution interaction. 
Additional scientific criteria that can be used by those skilled in the art 
for selecting a stabilizing material include the following: (a) the 
material possesses a high degree of substitution; for example, the 
material has undergone etherification or esterification, particularly 
acylation towards or to completion with membrane formed containing these 
stabilizers demonstrates increased resistance to hydrolysis and increased 
rejection of agent, (b) the stabilizer exhibits a flux decrease with 
increasing molecular size of the substituting group, such as an ether or 
ester group, (c) the stabilizer exhibits a flux decrease proportional to 
the increase in size of the substituent; for example, the decrease occurs 
as the number of carbon atoms increase in a hydrocarbon moiety such as an 
alkyl or alkoxy moiety, (d) the stabilizer exhibits increased stability 
with an increase in the degree of substitution of hydrophobic ether and 
larger hydrophobic ester groups with an accompanying decrease in the 
degree of substitution of smaller hydrophilic ester groups, and (e) the 
stabilizer exhibits a flux decrease as the number of polar ionic groups 
bonded to the stabilizer decrease. 
The expression "flux enhancing agent" as used herein means a compound that 
when added to a semipermeable wall forming material assists in regulating 
the fluid permeability or liquid flux through the wall. The agent can be 
preselected to increase or decrease the liquid flow through the wall. 
Agents that produce a marked increase in permeability to fluids such as 
water, are often essentially hydrophilic, while those that produce a 
marked decrease to fluids such as water, are essentially hydrophobic. The 
flux enhancer in some embodiments also can increase the flexibility of the 
wall. The flux enhancers, in one embodiment, are 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, 
4000, and 6000 of the formula H-(OCH.sub.2 CH.sub.2).sub.n OH wherein n is 
respectively 5 to 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 the low molecular weight 
glycols such as polypropylene, polybutylene and polyamylene. 
The flux enhancing 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 carbon atoms such as glycerine, 
1,2,3-butanetriol, 1,2,3-pentanetriol, 1,2,4-hexanetriol and 
1,3,6-hexanetroil. 
Other flux enhancers 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 
flux enhancers are ethylene glycol dipropionate, ethylene glycol butyrate, 
ethylene glycol diacetate, triethylene glycol diacetate, dutylene glycol 
diproprionate, polyester of ethylene glycol with succinic acid, polyester 
of diethylene glycol with maleic acid and polyester of triethylene glycol 
with adipic acid. Also, certain stabilizers in some embodiments can serve 
as a flux enhancer, particularly when it has a low D.S. of acyl moieties. 
Suitable flux enhancers for compounding with a material to increase its 
fluid permeability can be selected by blending known amounts of an 
enhancer with the material, casting the blends into thin films, and then 
measuring the increase in permeability towards the fluid found in the 
environment of use. For example, to two separate batches of wall forming 
cellulose acetate having an acetyl content of 32% and 39.8% were added 1,2 
and 3 grams of flux enhancer polyethylene glycol having a molecular weight 
of 400 and the ingredients blended in a high shear blender in the presence 
of 120 ml of dimethyl formamide to yield six blends. Next, the blends were 
solvent cast with a Gardner knife and dried in an over for 7 days at 
50.degree. C. The water permeability of the six films was measured in the 
osmosis cell described above and the results recorded in FIG. 9. In the 
figure, the triangle represents cellulose acetate 32% and the circle 
represents cellulose acetate 39.8%. Also, as recorded on the ordinate, 
k.sub.o indicates the water permeability through cellulose acetate 32% 
free of flux enhancer and cellulose acetate 39.8% that did not contain any 
flux enhancer, and k indicates the water permeability through cellulose 
acetate 32% and cellulose acetate 39.8% where both contained the flux 
enhancer. The positive integers 10, 20, 30 and 40, recorded on the 
abscissa, indicate the percent of flux enhancer in the film. Using the 
above technique, specific flux enhancers for blending with specific 
materials to regulate the permeability can be selected for making the 
desired osmotic device. The amount of flux enhancer added to a material 
generally is an amount sufficient to produce the desired permeability, and 
it will vary according to the wall forming material and the flux enhancer 
used to regulate the permeability. Usually, from 0.001 parts up to 50 
parts of flux enhancer can be used to achieve the desired results, with a 
presently preferred range consisting of 0.1 part up to 30 parts of 
enhancer or mixtures thereof for 100 parts of wall forming material. 
Exemplary plasticizers suitable for the present purpose generically include 
plasticizers that lower the temperature of the second-order phase 
transition of the wall or the elastic modulus thereof; and also increase 
the workability of the wall, its flexibility and its permeability to 
fluid. Plasticizers operable for the present purpose include both cyclic 
plasticizers and acyclic plasticizers. Typical plasticizers are those 
selected from the group consisting of phthalates, phosphates, citrates, 
adipates, tartrates, sebacates, succinates, glycolates, glycerolates, 
benzoates, myristates, sulfonamides, and halogenated phenyls. Generally, 
from 0.01 to 50 parts, preferably from 2 to 30 parts, of a plasticizer or 
a mixture of plasticizers are incorporated into 100 parts of wall forming 
material. 
Exemplary plasticizers include dialkyl phthalates, dicycloalkyl phthalates, 
diaryl phthalates and mixed alkylaryl 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 and triphenyl phosphate; alkyl citrate and citrate esters such 
as tribuyl citrate, triethyl citrate, and acetyl triethyl citrate; alkyl 
adipates such as dioctyl adipate, diethyl adipate and 
di-(2-methyoxyethyl)-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 phthalyl ethyl glycolate, butyl 
phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol 
dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate 
and triethylene glycol diproprionate. Other plasticizers include camphor, 
N-ethyl-(o- and p-toluene) sulfonamide, chlorinated biphenyl, 
benzophenone, N-cyclohexyl-p-toluene sulfonamide, and substituted 
epoxides. 
Suitable plasticizers can be selected for blending with the wall forming 
materials by selecting plasticizers 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 their 
strong tendency to remain in the plasticized wal, impart flexibility to 
the material and are non-toxic to animals, humans, avians, fishes and 
reptiles. Procedures for selecting a plasticizer 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. Also, a detailed description pertaining to the measurement of 
plasticizer properties including solvent parameters and compatibility such 
as the Hildebrand solubility parameter .delta., the Flory-Huggins 
interaction parameter .mu., and the cohesive-energy density, CED, 
parameters are disclosed in Plasticization and Plasticizer Processes, 
Advances in Chemistry Series 48, Chapter 1, pages 1 to 26, 1965, published 
by the American Chemical Society. The amount of plasticizer added 
generally is an amount sufficient to produce the desired wall and it will 
vary according to the plasticizer and the materials. Usually about 0.001 
part up to 50 parts of plasticizer can be used for 100 parts of wall 
material with a presently preferred range of 0.1 part to 20 parts of 
plasticizer, or mixtures thereof for 100 parts of wall materials. 
Dispersants useful for the present purpose are those dispersants, when 
added to a wall forming material and other materials, aid in producing an 
integral composite that is useful for making the operative wall of a 
device. The dispersants act by regulating the surface energy of materials 
to improve their blending into the composite. This latter material is used 
for manufacturing devices that maintain their integrity in the environment 
of use during the agent release period. Generally, the dispersants are 
amphipathic molecules comprised of a hydrophobic part and a hydrophilic 
part. The dispersants can be anionic, cationic, nonionic or amphoteric, 
and they include anionics such as sulfated esters, amides, alcohols, 
ethers and carboxylic acids; sulfonated aromatic hydrocarbons, aliphatic 
hydrocarbons, esters and ethers; acylated amino acids and peptides; and 
metal alkyl phosphates; cationic dispersants such as primary, secondary, 
tertiary and quaternary alkylammonium salts; acylated polyamines; and 
salts of heterocyclic amines, arylammonium dispersants such as esters of 
polyhydric alcohols; alkoxylated amines; polyoxyalkylene; esters and 
ethers of polyoxyalkylene glycols; alkanolamine fatty acid condensates; 
tertiary acetylamic glycols; and dialkyl polyoxyalkylene phosphates; and 
ampholytics such as betamines; and amino acids. 
Typical dispersants include polyoxyethylenated glycerol ricinoleate; 
polyoxyethylenated castor oil having from 9 to 52 moles of ethylene oxide; 
glycerol mannitan laurate, and glycerol (sorbitan oleates, stearates or 
laurates); polyoxyethylenated sorbitan laurate, palmitate, stearate, 
oleate or hexaolate having from 5 to 20 moles of ethylene oxide; mono-, 
di- and poly-ethylene glycol stearates, laurates, oleates, myristates, 
behenates or ricinoleates; propylene glycol carboxylic acid esters; 
sorbitan laurate, palmitate, oleate, and stearate; polyoxyethylenated 
octyl, nonyl, decyl, and dodecylphenols having 1 to 100 moles of ethylene 
oxide; polyoxyethylenated nonyl, lauryl, decyl, cetyl, oleyl and stearyl 
alcohols having from 3 to 50 moles of ethylene oxide; polyoxypropylene 
glycols having from 3 to 300 moles of ethylene oxide; sodium salt of 
sulfated propyl oleate; sodium di(heptyl)-sulfosuccinate; potassium 
xylenesulfonate; 1:1 myristic acid diethanolamide; 
N-coco-.beta.-aminopropionic acid; bis-(2-hydroxyethyl)tallowamine oxide; 
(diisobutyl-phenoxyethoxyethyl)dimethylbenzylammonium halide; 
N,N'-polyoxypropylenated ethylenediamine having a molecular weight from 
500 to 3000; tetra-alkylammonium salts with up to 26 carbon atoms in the 
cation; sodium or potassium salt of polypeptide cocoanut, oleic or 
undecylenic acid condensate; metal salts of N-acylated short chain 
aminosulfonic acids; soybean phosphatides; and sulfobetaine. 
Suitable dispersants can be selected from the above and from other 
dispersants for blending with wall forming materials by using the 
dispersant's hydrophile-lipophile balance number, HLB. This number 
represents the proportion between the weight percentages of hydrophilic 
and lipophilic groups in a dispersant. In use, the number indicates the 
behavior of the dispersant, that is, the higher the number the more 
hydrophilic the dispersant and the lower the number the more lipophilic 
the dispersant. The required HLB number for blending wall forming 
materials is determined by selecting a dispersant with a known number, 
blending it with the materials and observing the results. A homogenous 
composite is formed with the correct number, while a heterogenous mixture 
indicates a different number is needed. This new number can be selected by 
using the prior number as a guide. The HLB number is known to the art for 
many dispersants, and they can be experimentally determined according to 
the procedure in J. Soc. Cosmetic Chem., Vol. 1, pages 311 to 326, 1949, 
or it can be calculated by using the procedure in J. Soc. Cosmetic Chem., 
Vol. 5, pages 249 to 256, 1954, and in Am. Perfumer Essent. Oil Rev., 
Vol. 65, pages 26 to 29, 1955. Typical HLB numbers are set forth in Table 
1. Generally a number of 10 or less indicates lipophilic behavior and 10 
or more indicates hydrophilic behavior. Also, HLB numbers are 
algebraically additive. Thus, by using a low number with a high number, 
blends of dispersants can be prepared having numbers intermediate between 
the two numbers. The amount of dispersant needed is an amount that when 
blended with wall forming materils will form the desired wall composite, 
and it will vary according to the particular 
TABLE 1 
______________________________________ 
DISPERSANT HLB NUMBER 
______________________________________ 
Sorbitan trioleate 1.8 
Polyoxyethylene sorbitol beeswax 
2.0 
Sorbitan tristearate 2.1 
Polyoxyethylene sorbitol hexastearate 
2.6 
Ethylene glycol fatty acid ester 
2.7 
Propylene glycol fatty acid ester 
3.4 
Propylene glycol monostearate 
3.4 
Ethylene glycol fatty acid ester 
3.6 
Glycerol monostearate 3.8 
Sorbitan monooleate 4.3 
Propylene glycol monolaurate 
4.5 
Diethylene glycol fatty acid ester 
5.0 
Sorbitan monopalmitate 6.7 
Polyoxyethylene dioleate 
7.5 
Polyoxypropylene mannitol dioleate 
8.0 
Sorbitan monolaurate 8.6 
Polyoxyethylene lauryl ether 
9.5 
Polyoxyethylene sorbitan monolaurate 
10.0 
Polyoxyethylene lanolin derivative 
11.0 
Polyoxyethylene glycol 400 monooleate 
11.4 
Triethanolamine oleate 12.0 
Polyoxyethylene nonyl phenol 
13.0 
Polyoxyethylene sorbitan monolaurate 
13.3 
Polyoxyethylene sorbitol lanolin 
14.0 
Polyoxyethylene stearyl alcohol 
15.3 
Polyoxyethylene 20 cetyl ether 
15.7 
Polyoxyethylene 40 stearate 
16.9 
Polyoxyethylene monostearate 
17.9 
Sodium oleate 18.0 
Potassium oleate 20.0 
______________________________________ 
dispersant and materials that are blended to form the wall. Generally, the 
amount of dispersant will range from about 0.001 parts up to 40 parts for 
100 parts of wall with a presently preferred range of 0.1 part to 15 parts 
of dispersant or mixtures thereof, for 100 parts of wall. 
Exemplary solvents suitable for manufacturing the wall of the osmotic 
device include inert inorganic and organic solvents that do not adversely 
harm the wall, and the materials forming the final wall. 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 alochol, methyl acetate, ethyl 
acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, 
methyl propyl ketone, n-hexane, ethyl lactate, 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, cyclooctane, dimethyl bormamide, 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. Illustative of mixed solvents are acetone-methanol (80:20), 
acetone-ethanol (90:10), methylene dichloride-methanol (80:20), 
nitroethane-ethanol (50:50), nitroethane-ethanol (80:20), ethyl 
acetate-ethanol (80:20), ethylene dichloride-methanol (80:20), 
methylenedichloride-methanol (78:22), acetone-water (90:10), 
chloroform-ethanol (80:20), methylene-dichloride-ethanol (79:21), 
methylene chloride-methanol-water (75:22:3), carbontetrachloride-methanol 
(70:30), expressed as (weight:weight), and the like. 
The expresson "passageway" as used herein comprises means and methods 
suitable for releasing the agent from the device. The expression includes 
an aperture, orifice or bore through the wall formed by mechanical 
procedures or by eroding an erodible element, such as a 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. No. 3,845,770 and in U.S. Pat. No. 3,916,899. 
The osmotically effective compounds 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 across the composite wall of 
the device. The compounds are used mixed with an agent that has limited 
solubility in the external fluid with the compound forming a saturated 
solution containing agent that is osmotically delivered from the device. 
The phrase "limited solubility" as used herein means the agent has a 
solubility of about less than 1% by weight in the external fluid. The 
compounds are used by homogenously or heterogenously mixing the compound 
or a mixture of compounds with an agent, either before they are charged 
into the reservoir, or by self-mixing after they are charged into the 
reservoir. In operation, these compounds attract fluid into the device 
producing a solution of compound which is delivered from the device 
concomitantly transporting undissolved and dissolved agent to the exterior 
of the device. Osmotically effective compounds 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 bicarbonate, sodium sulfate, 
calcium sulfate, potassium acid phosphate, calcium lactate, d-mannitol, 
urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as 
raffinose, sucrose, glucose, .alpha.-d-lactose monohydrate, and mixtures 
thereof. The compound is initially present in excess and it can be in any 
physical form such as particle, crystal, pellet, tablet, strip, film or 
granule. The osmotic pressure of saturated solutions of various 
osmotically effective compounds and for mixtures of compounds at 
37.degree. C., in water, is listed in Table 2. In the table, the osmotic 
pressure .pi., is in atmospheres, atm. The osmotic pressure is measured in 
a commercially available osmometer that measures the vapor pressure 
difference between pure water and the solution to be analyzed, and 
according to standard thermodynamic principles, the vapor pressure ratio 
is converted into osmotic pressure difference. In Table 2, osmotic 
pressures of from 20 atm to 500 atm are set forth; of course, the 
invention includes the use of lower osmotic pressures from greater than 
zero, and higher osmotic pressures than those set forth by way of example 
in Table 2. For example, in the gastrointestinal tract, the osmotic 
pressure gradient across the wall in the compartment will be from greater 
than 0 up to 500 atm per membrane thickness. That is, the osmotic pressure 
in the compartment will be in excess of 8 atm up to 500 atm. The osmometer 
used for the present measurements is identified as Model 302B, Vapor 
Pressure Osmometer, manufactured by the Hewlett Packard Co., Avondale, 
Penna. 
TABLE 2 
______________________________________ 
OSMOTIC PRESSURE 
COMPOUND OR MIXTURE (atm) 
______________________________________ 
Lactose-Fructose 500 
Dextrose-Fructose 450 
Sucrose-Fructose 430 
Mannitol-Fructose 415 
Sodium Chloride 356 
Fructose 355 
Lactose-Sucrose 250 
Potassium Chloride 245 
Lactose-Dextrose 225 
Mannitol-Dextrose 225 
Dextrose-Sucrose 190 
Mannitol-Sucrose 170 
Sucrose 150 
Mannitol-Lactose 130 
Dextrose 82 
Potassium Sulfate 39 
Mannitol 38 
Sodium Phosphate Tribasic . 12H.sub.2 O 
36 
Sodium Phosphate Dibasic . 7H.sub.2 O 
31 
Sodium Phosphate Dibasic . 12H.sub.2 O 
31 
Sodium Phosphate Dibasic Anydrous 
29 
Sodium Phosphate Monobasic . H.sub.2 O 
28 
______________________________________ 
The expression "active agent" as used herein broadly includes any 
compound, composition of matter or mixture thereof that can be delivered 
from the device to produce a beneficial and useful result. The agent can 
be soluble in a fluid that enters the reservoir and functions as an 
osmotically effective solute, or it can have limited solubility in the 
fluid and be mixed with an osmotically effective compound soluble in fluid 
that is delivered from the device. The active agent includes pesticides, 
herbicides, germicides, biocides, algicides, rodenticides, fungicides, 
insecticides, anti-oxidants, plant growth promoters, plant growth 
inhibitors, 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-organizm 
attenuators, and other agents that benefit the environment of use. 
In the specification and the accompanying claims, the term "drug" includes 
any physiologically or pharmacologically active substance that produces a 
localized or systemic effect or effects in animals, including 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, and to fishes, 
reptiles and zoo 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, 
including pentobarbital sodium, phenobarbital, secobarbital, thiopental 
and mixtures thereof, heterocyclic hypnotics such as dioxopiperidines and 
glutarimides, hypnotics and sedatives such as amides and ureas, 
exemplified by diethylisovaleramide and .alpha.-bromoisovaleryl urea, 
hypnotic and sedative urethanes and disulfanes, psychic energizers such as 
isocarboxazid, nialamide, phenelzine, imipramine, tranylcypromine and 
pargylene, tranquilizers such as chloropromazine, promazine, fluphenazine, 
reserpine, deserpidine, meprobamate, benzodiazepines such as 
chlordiazepoxide, anticonvulsants such as primidone, enitabas, 
diphenylhydantoin, ethltion, pheneturide and ethosuximide, muscle 
relaxants and antiparkinson agents such as mephenesin, methocarbomal, 
trihexylphenidyl, biperiden, levo-dopa also known as L-dopa and 
L-.beta.-3-4-dihydroxyphenylalanine, analgesics such as morphine, codeine, 
meperidine, nalorphine, antipyretics and anti-inflammatory agents such as 
aspirin, salicylamide, colchicine and sodium salicylamide, local 
anesthetics such as procaine, lidocaine, naepaine, piperocaine, tetracaine 
and dibucane, antispasmodics and muscle contractants such as atropine, 
scopolamine, methscopolamine, oxyphenomium, papaverine, prostaglandins 
such as PGE.sub.1, PGE.sub.2, PGF.sub.1.alpha.', PFG.sub.2.alpha. and 
PGA, anti-microbials such as penicillin, tetracycline, oxytetracycline, 
chlorotetracycline, chloramphenicol and sulfonamides, anti-malarials such 
as 4-aminoquinolines, 8-aminoquinolines and pyrimethamine, hormonal agents 
such as prednisolone, cortisone, cortisol and triamcinolone, androgenic 
steroids such as methyltestosterone, and fluoxmesterone, estrogenic 
steroids such as 17.beta.-estradiol, .alpha.-estradiol, estriol, 
.alpha.-estradiol 3-benzoate, and 17-ethynyl estradiol-3-methyl ether, 
progestational steroids such as progesterone, 
19-nor-pregn-4-ene-3,20-dione, 17-hydroxy-19-nor-17-.alpha.-pregn-5(10 
)-ene-20-yn-3-one, 17.alpha.-ethynyl-17-hydroxy-5(10)-estren-3-one, and 
9.beta., 10.alpha.-pregna-4,6-diene-3,20-dione, sympathomimetic drugs such 
epinephrine, amphetamine, ephedrine and norephedrine, cardiovascular drugs 
such as procainamide, procainamide hydrochloride, amyl nitrile, 
nitroglycerin, dipyredamole, sodium nitrate and mannitol nitrate, 
diuretics such as chlorathiazide, acetazolamide, methazolamide and 
flumethiazide, antiparasitics such as bephenium, hydroxynaphthoate, 
dichlorophen and dapsone, neoplastics such as mechlorethamine, uracil 
mustard, 5-fluorouracil, 6-thioguanine and procarbazine, hypoglycemic 
drugs such as insulin, isophane insulin, protamine zinc insulin 
suspension, globin zinc insulin, extended insulin zinc suspension, 
tolbutamide, acetohexamide, tolazamide and chlorpropamide, nutritional 
agents such as ascorbic acid, niacin, nicotinamide, folic acid, choline, 
biotin, pantothenic acid, and vitamine B.sub.12, essential amino acids, 
essential fats, eye drugs such as pilocarpine, pilocarpine salts such as 
pilocarpine nitrate, pilocarpine hydrochloride, dichlorphenamide, 
atropine, atropine sulfate, scopolamine and eserine salicylate, and 
electrolytes such as calcium gluconate, calcium lactate, potassium 
chloride, potassium sulfate, sodium chloride, potassium fluoride, sodium 
fluoride, ferrous lactate, ferrous gluconate, ferrous sulfate, ferrous 
fumurate and sodium lactate. The beneficial drugs are known to the art in 
Remington's Pharmaceutical Sciences, 14th Ed., 1970, published by Mack 
Publishing Co., Easton, Penna.; and in The Pharmacological Basis of 
Therapeutics by Goodman and Gilman, 4th Ed., 1970, published by The 
MacMillan Company, London. 
The drug can also be in various forms, such as uncharged molecules, 
molecular complexes, pharmacologically acceptable 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 esters, 
ethers and amides which have solubility characteristics suitable for use 
herein can be used alone or mixed with other drugs. Also a drug that is 
water insoluble can be used in a form that is a water soluble derivative 
thereof to effectively 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 form, or to a biologically active form. The 
agent can be in the reservoir as a solution, dispersion, paste, cream, 
particle, granule, emulsion, suspension or powder. Also, the agent can be 
mixed with a binder, dispersant, emulsifier or wetting agent and dyes. 
The amount of agent present in the device is initially in excess of the 
amount that can be dissolved in the fluid that enters the reservoir. Under 
this physical state when the agent is in excess, the device 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 reservoir to form solutions containing different 
concentrations of agent for delivery from the device. Generally, the 
device can house from 0.05 ng to 5 grams or more, with individual devices 
containing, for example, 25 ng, 1 mg, 5 mg, 250 mg, 500 mg, 1.5 g, and the 
like. 
The solubility of an agent in an external fluid 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 of agent 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 stirring, 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 osmotically effective compound 
optionally may not be needed; if the agent has limited solubility in the 
fluid, then an osmotically effective compound can be incorporated into the 
device. Numerous other methods are available for the determination of the 
solubility of an agent in a fluid. Typical methods used for the 
measurement of solubility are chemical analysis, ultra violet 
spectrometry, density, refractive index 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 by Pergamon Press, Inc. 
The devices of the invention are manufactured by standard techniques. For 
example, in one embodiment the agent and other ingredients that may be 
housed in the compartment and a solvent are mixed into a solid, semi-solid 
or gel form by conventional methods such as ballmilling, calendering, 
stirring, or rollmilling and then pressed into a preselected shape. The 
wall forming the devices can be applied by molding, spraying or dipping 
the pressed shape into wall forming materials. In another embodiment, a 
wall can be cast into a film, shaped to the desired dimensions, partially 
sealed to define a hollow compartment that is filled with agent, and then 
closed. The device also can be manufactured with an empty compartment that 
is filled through the passageway. High frequency electronic techniques can 
be used to provide devices with walls having clean edges. Another, and 
presently preferred, technique that can be used is the air suspension 
procedure. This procedure consists in suspending and tumbling the pressed 
agent in a current of air and the wall forming composite until the wall is 
applied to the agent. The air suspension procedure is described in U.S. 
Pat. No. 2,799,241; J. Am. Pharm. Assoc., Vol. 48, pages 451 to 459, 1959; 
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, Penna. 
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 
The permeability of a series of walls formed of blends of materials was 
illustrated by preparing and measuring their permeability to water as 
follows: To a first mixture consisting of 76.6 parts of wall forming 
cellulose acetate having an acetyl content of 38.3% and 12.76 parts of the 
flux enhancer polyethylene glycol having a molecular weight of 400 
dissolved in a solvent consisting of 80 parts of methylene chloride and 20 
parts of methanol was added in small amounts and with continuous stirring 
a second mixture consisting of 8.52 parts hydroxybutyl methylcellulose 
which functions as both a stabilizer and a flux enhancer and 2.12 parts of 
the dispersant polyoxypropylene glycol having a molecular weight of 950 
dissolved in a solvent consisting of 80 parts methylene chloride and 20 
parts of methanol and the stirring continued until the two mixtures were 
thoroughly blended. Then, an additional solvent consisting of 90 parts of 
acetone and 10 parts of water was added to the blend and all the materials 
stirred for 30 minutes at room temperature, 22.degree. C., and atmospheric 
pressure until a homogeneous composite was formed. 
Next, a film of 2.5 mils (dry thickness) of the composite was cast with a 
Gardner film-casting blade on a borosilicate glass substrate warmed to 
40.degree. C. The film was dried while on the substrate in an oven at 
70.degree. C. for 120 hours. Then, the film was stripped from the 
substrate and it was observed to be optically clear. The water 
transmission rate of the film was measured using potassium chloride and 
sodium acetazolamide in the osmosis cell at 37.degree. C., and the results 
recorded in FIG. 10, discussed below. 
EXAMPLE 2 
The procedure of Example 1 was repeated in this example and all conditions 
were as described except that the film consisted of 68.10 parts of 
cellulose acetate having an acetyl content of 38.3%, 17.02 parts of 
hydroxybutyl methylcellulose, 12.76 parts of polyethylene glycol having a 
molecular weight of 400 and 2.12 parts of polyoxypropylene glycol having a 
molecular weight of 950. The permeability of the film to water using the 
same osmotic attractants was measured and the results recorded in FIG. 10, 
discussed below. 
EXAMPLE 3 
The procedure of Example 1 was repeated in this example with all conditions 
as described except that the film consisted of 59.60 parts of cellulose 
acetate having an acetyl content of 38.3, 25.52 parts of hydroxybutyl 
methylcellulose, 12.76 parts of polyethylene glycol having a molecular 
weight of 400 and 2.12 parts of polyoxypropylene glycol having a molecular 
weight of 950. The permeability of the film to water using the same 
osmotic attractants was measured and the results recorded in FIG. 10. 
In FIG. 10, the permeabilities through the films prepared according to 
Examples 1, 2 and 3 are plotted as a function of the hydroxybutyl 
methylcellulose content of the film. The numbers on the abscissa represent 
the percent of wall stabilizer hydroxybutyl methylcellulose in the three 
films, and the numbers on the ordinate represent the permeability 
k.pi.(cm.sup.3.mil/cm.sup.2.hr) through the films. The line with the 
circles indicates potassium chloride as the osmotic attractant and the 
lines with triangles indicate sodium acetazolamide as the attractant. 
EXAMPLE 4 
The stability of a series of walls formed of blends of materials was 
demonstrated by preparing the walls and measuring their stability in the 
presence of an osmotic attractant. The walls used were prepared according 
to the procedures of Examples 1, 2 and 3. Their stability was determined 
by measuring their permeability to water using sodium acetazolamide as the 
osmotic attractant in osmosis cells at 37.degree. C. The results are 
plotted in FIG. 11. In the figure the numbers on the abscissa represent 
the time in minutes the film is in contact with a saturated solution of 
sodium acetazolamide and the numbers on the ordinate represent the water 
transmission rate, k.pi.(cm.sup.3.mil/cm.sup.2. hr) through the film. The 
line with circles represents a film prepared according to Example 1. The 
line with triangles represents a film prepared according to Example 2. The 
line with squares represents a film prepared according to Example 3. 
EXAMPLE 5 
The inertness (physical and chemical stability) in the presence of a 
caustic-acting osmotic attractant, and the permeability to an aqueous 
medium of a series of composite walls as a function of the degree of 
substitution of the wall forming material and the concentration of the 
stabilizer and flux enhancer in the wall were determined by preparing and 
analyzing the walls according to the procedure of Example 1. The results 
obtained are presented in Table 3. In the table the meaning of the terms 
and the abbreviations is as follows: the number in the column headed 
"Walls" indicates a series of composite walls and the small letters within 
a series indicate the different compositions of particular walls made in a 
series; the term "Composition" indicates the materials and percent thereof 
for the walls; (the letters in a series refer to embodiments of the 
compositions in a series, and when they are used, they indicate an 
ingredient that is present in different amounts). In the table the 
representations are as follows: in compositions 1 through 3 the number 
85.12 indicates the amount of cellulose acetate or a blend of cellulose 
acetate plus the amount of H.B.M.C. present in a composition; the 
expression (85.12-x)% indicates the percent cellulose acetate present as a 
sinle ingredient or as a blend of cellulose acetates, and x indicates the 
percent H.B.M.C. present in each composition; in composition 4 the number 
72.38 indicates the amount of cellulose acetate plus the amount of P.E.G. 
present in a composition; the expression (72.38-x)% indicates the percent 
cellulose acetate present, and x is the percent P.E.G.; "C.A." means 
cellulose acetate; "D.S." is the degree of substitution; "H.B.M.C." is 
hydroxybutyl methylcellulose; "P.E.G." and "polyethylene glycol" indicate 
polyethylene glycol having a molecular weight of 400; "Polyoxyporpylene 
glycol" indicates the dispersant having a molecular weight of 950; 
"K.sub.2 SO.sub.4 " is potassium sulfate having an osmotic pressure of 39 
atmospheres; "T.M." is the caustic-acting osmotic attractant theophylline 
monoethanolamine having an osmotic pressure of 55 atmosphers; and "k.pi." 
is the water transmission of the wall measured in 
cm.sup.3.mil/cm.sup.2.hr. 
TABLE 3 
______________________________________ 
Osmotic 
Wall Composition Attractant 
k.pi. 
______________________________________ 
1 Cellulose acetate D.S. 1.75 
(85.12 - x)%, plus Polyethylene 
glycol 12.76%, Polyoxypropylene 
glycol 2.12%, and Hydroxybutyl 
methylcellulose x%. 
a) C.A. 76.60% + H.B.M.C. 8.52% 
K.sub.2 SO.sub.4 
0.15 
b) C.A. 68.10% + H.B.M.C. 17.02% 
K.sub.2 SO.sub.4 
0.20 
c) C.A. 59.60% + H.B.M.C. 25.52% 
K.sub.2 SO.sub.4 
0.25 
2 Cellulose acetate consisting of 
a blend of 67.19% Cellulose 
acetate with D.S. 1.75 and 32.81% 
Cellulose acetate with D.S. 2.3 
(85.12 - x)%, plus Polyethylene 
glycol 12.76%, Polyoxypropylene 
glycol 2.12%, and Hydroxybutyl 
methylcellulose x%. 
a) C.A. 76.60% + H.B.M.C. 8.52% 
T.M. 0.13 
b) C.A. 68.10% + H.B.M.C. 17.02% 
T.M. 0.18 
c) C.A. 59.60% + H.B.M.C. 25.52% 
T.M. 0.215 
3 Cellulose acetic consisting of 
a blend of 50% Cellulose acetate 
with D.S. 1.75 and 50% Cellulose 
acetate with D.S. 2.3 (85.12 - x)%, 
plus Polyethylene glycol 12.76%, 
Polyoxypropylene glycol 2.12%, 
Hydroxybutyl methylcellulose x%. 
a) C.A. 76.60% + H.B.M.C. 8.52% 
T.M. 0.1 
b) C.A. 68.10% + H.B.M.C. 17.02% 
T.M. 0.14 
c) C.A. 59.60% + H.B.M.C. 25.52% 
T.M. 0.17 
4 Cellulose acetate D.S. 1.75 
(72.38 - x)%, plus Hydroxy- 
butyl methylcellulose 25.5%, 
Polyoxypropylene glycol 2.12%, 
and Polyethylene glycol x%. 
a) C.A. 66.38% + P.E.G. 6.00% 
K.sub.2 SO.sub.4 
0.144 
b) C.A. 59.63% + P.E.G. 12.75% 
K.sub.2 SO.sub.4 
0.24 
c) C.A. 56.48% + P.E.G. 15.90% 
K.sub.2 SO.sub.4 
0.27 
d) C.A. 46.88% + P.E.G. 25.50% 
K.sub.2 SO.sub.4 
0.31 
5 64% Cellulose acetate blend of 
67.19% Cellulose acetate with 
D.S. 1.75 and 32.81% Cellulose 
acetate with D.S. 2.3, Hydroxy- 
T.M. 0.19 
butyl methycellulose 22%, 
Polyethylene glycol 12%, and 
Polyoxypropylene glycol 2%. 
______________________________________ 
EXAMPLE 6 
The permeability of a film consisting of at least two cellulose acetates 
each having a different acetyl content was determined by preparing a film 
and measuring its permeability according to the procedure of Example 1. 
The cellulose acetates used has an acetyl content ranging from 23% to 
44.8% and the amount used ranged from 0.1% to 99.9% of a cellulose acetate 
having an acetyl content of from 23% up to 32% and from 99.9% to 0.1% of a 
cellulose acetate having an acetyl content from 32% up to 44.8%. A 
plurality of films was prepared according to the example and they had the 
following composition: 
(a) a film comprising 85.12% cellulose acetate blend consisting of 67.19% 
cellulose acetate having an acetyl content of 32% and 32.81% cellulose 
acetate having an acetyl content of 38.3%, 12.76% polyethylene glycol 
having a molecular weight of 400 and 2.12% polyoxypropylene glycol having 
a molecular weight of 950; 
(b) a film comprising 76.60% cellulose acetate of the blend as set forth in 
(a), polyethylene glycol and polyoxyporpylene glycol the same as in (a), 
and additionally, 8.52% of hydroxybutyl methylcellulose; 
(c) a film comprising 68.10% cellulose acetate blend of (a), polyethylene 
glycol and polyoxypropylene glycol the same as (a), and 17.02% of 
hydroxybutyl methylcellulose, and 
(d) a film comprising 50.60% ceelulose acetate blend of (a), polyethylene 
glycol and polyoxypropylene glycol the same as (a), and 25.52% of 
hydroxybutyl methylcellulose. 
The ratio of the permeability of the films to water is plotted in FIG. 12. 
In this figure the numbers along the abscissa represent the percent 
hydroxybutyl methylcellulose in the film and the numbers along the 
ordinate indicate the permeability ratio k/k.sub.o. The values of 
k/k.sub.o were obtained by dividing the measured permeability of film (a) 
into each of (a), (b), (c), and (d) thereby expressing the permeability 
ratio of the films as a function of their hydroxybutyl methylcellulose 
content. In the figures, k.sub.o is the permeability of the film to water 
with the film containing a zero concentration of H.B.M.C. 
EXAMPLE 7 
The fluid permeability of cellulose acetate films as a function of the 
acetyl content of each film in the presence of increasing amounts of 
hydroxybutyl methylcellulose was determined by preparing a multiplicity of 
films and measuring their permeability to water. The films were made and 
the water transmission of each film measured by following the procedures 
of Examples 1 and 6. The results obtained were recorded in FIG. 13. In 
this figure the number along the abscissa represents the ester content; 
that is, the percent acetyl content of the films, and the numbers along 
the ordinate represent the fluid permeability k expressed as cm.sup.3 
.multidot.mil/cm.sup.2 .multidot.hr atm through the films. The letters 
C.sub.o through C.sub.4 indicate five series of films comprised of the 
following materials: C.sub.o represents a plurality of films consisting of 
100 percent cellulose acetate with acetyl contents ranging from 32 to 45 
percent; C.sub.1 represents a plurality of films consisting of 85.12 
percent cellulose acetate, 12.76 percent polyethylene glycol having a 
molecular weight of 400 and 2.12 percent polyoxypropylene glycol having a 
molecular weight of 950; C.sub.2 represents films consisting of 76.60% 
cellulose acetate, the same amount of polyethylene glycol and 
polyoxypropylene glycol of C.sub.1, and 8.52% hyroxybutyl methylcellulose; 
C.sub.3 represents films consisting of 68.10 percent cellulose acetate, 
the same amount of polyethylene glycol and polyoxypropylene glycol of 
C.sub.1, and 17.02% hydroxybutyl methylcellulose; and C.sub.4 represents 
films consisting of 59.60% cellulose acetate, the same amount of 
polyethylene glycol and polyoxypropylene glycol as in C.sub.1, and 25.52% 
of hydroxybutyl methylcellulose. 
EXAMPLE 8 
A plurality of films was prepared and their k.pi. values measured by 
following the procedures of Examples 1 and 6. The results obtained were 
recorded in Table 4. In the table the abbreviations have the following 
significance: C.A. indicates cellulose acetate; the numbers 32 to 38.3 
indicate in percent the acetyl content in the cellulose polymer; A.sub.o 
indicates the film additionally contains 12.76 percent polyethylene glycol 
having a molecular weight of 400 and 2.12 percent polyoxypropylene glycol 
having a molecular weight of 950; A.sub.1 indicates the film additionally 
contains the same amount of the polyethylene glycol and polyoxypropylene 
glycol of A.sub.o and it also contains 8.5 percent hydroxybutyl 
methylcellulose; A.sub.2 indicates the film additionally contains the same 
amount of the polyethylene glycol and polyoxypropylene glycol of A.sub.o 
and it also contains 17.02% hydroxybutyl methylcellulose; A.sub.3 
indicates the film contains the polyethylene glycol and polyoxypropylene 
glycol of A.sub.o and it also contains 25.52% hydroxybutyl 
methylcellulose; K.sub.2 SO.sub.4 is potassium sulfate; KC1 is potassium 
chloride; T.M. is theophylline monoethanolamine; the osmotic pressure .pi. 
is in atmospheres; k.pi. is the volume of water transported per unit time 
through a film of unit thickness per unit area expressed as cm.sup.3 
.multidot.mil/cm.sup.2 .multidot.hr; k is water permeability in cm.sup.3 
.multidot.mil/cm.sup.2 .multidot.hr .pi., obtained by dividing k.pi. by 
.pi.. 
TABLE 4 
______________________________________ 
Osmotic Osmotic 
Film Attractant 
Pressure .pi. 
k.pi. 
k 
______________________________________ 
CA 32 K.sub.2 SO.sub.4 
39 0.043 
1.10 .times. 10.sup.-3 
CA 32 KCl 245 0.27 1.10 .times. 10.sup.-3 
CA 32 T.M. 55 0.06 1.09 .times. 10.sup.-3 
CA 32 + A.sub.o 
K.sub.2 SO.sub.4 
39 0.1 2.56 .times. 10.sup.-3 
CA 32 + A.sub.1 
K.sub.2 SO.sub.4 
39 0.15 3.84 .times. 10.sup.-3 
CA 32 + A.sub.2 
K.sub.2 SO.sub.4 
39 0.2 5.12 .times. 10.sup.-3 
CA 32 + A.sub.3 
K.sub.2 SO.sub.4 
39 0.25 6.41 .times. 10.sup.-3 
CA 34.06 KCl 245 0.165 
6.73 .times. 10.sup.-4 
CA 34.06 T.M. 55 0.037 
6.72 .times. 10.sup.-4 
CA 34.06 + A.sub.0 
T.M. 55 0.085 
1.50 .times. 10.sup.-3 
CA 34.06 + A.sub.1 
T.M. 55 0.13 2.30 .times. 10.sup.-3 
CA 34.06 + A.sub.2 
T.M. 55 0.18 3.27 .times. 10.sup. -3 
CA 34.06 + A.sub.3 
T.M. 55 0.215 
3.90 .times. 10.sup.-3 
CA 35 T.M. 55 0.03 5.45 .times. 10.sup.-4 
CA 35 KCl 245 0.125 
5.10 .times. 10.sup.-4 
CA 35 + A.sub.0 
T.M. 55 0.07 1.27 .times. 10.sup.-3 
CA 35 + A.sub.1 
T.M. 55 0.1 1.80 .times. 10.sup.-3 
CA 35 + A.sub.2 
T.M. 55 0.14 2.50 .times. 10.sup.-3 
CA 35 + A.sub.3 
T.M. 55 0.17 3.10 .times. 10.sup.-3 
CA 38 KCl 245 0.053 
2.16 .times. 10.sup.-4 
CA 38.3 + A.sub.0 
KCl 245 0.13 5.30 .times. 10.sup.-4 
CA 38.3 + A.sub.1 
KCl 245 0.19 7.70 .times. 10.sup.-4 
CA 38.3 + A.sub.2 
KCl 245 0.26 1.06 .times. 10.sup.-3 
CA 38.3 + A.sub.3 
KCl 245 0.32 1.31 .times. 10.sup.-3 
______________________________________ 
EXAMPLE 9 
An osmotic therapeutic system for the controlled and continuous oral 
release of the beneficial agent sodium acetazolamide was made as follows: 
to 138 grams of wall forming cellulose acetate having an acetyl content of 
32% was added 73.6 grams of the stabilizer cellulose acetate having an 
acetyl content of 39.8%, 18.4 grams of the flux enhancer polyethylene 
glycol of the formula H-OCH.sub.2 CH.sub.2).sub.n OH wherein n is 8.2 to 
9.1 and 5520 grams of solvent consisting of acetone:water in the ratio of 
88.5:11.5 and the materials blended in a commercially available high shear 
blender. The materials were blended at room temperature and atmospheric 
pressure for 30 minutes to produce a homogenous blend that had a solid 
content of 4%. 
Next, 170 grams of sodium acetazolamide and 8.5 grams of the binder 5% 
(polyvinylpyrrolidone) in isopropyl alcohol were blended in a standard 
v-blender for 45 minutes to produce wet granules. The granules were dried 
in an oven at 50.degree. C. for 48 hours and passed through a standard No. 
30 mesh sieve. Then, 1.8 grams of the lubricant magnesium stearate were 
separately passed through the No. 30 sieve and the former granules mixed 
with the latter in the blender for about 30 minutes, or until a uniform 
mixture was obtained. The mixture was then compressed in a conventional 
Manesty tableting machine using a 5/16 inch diameter concave punch to 
produce compressed tablets having a hardness of about 9 kg as measured by 
a Strong-Cobb hardness tester. 
Next, the above prepared wall forming composite and the tablets were placed 
in a Wurster air suspension machine and the tablets air tumbled until they 
were uniformly coated. The tablets were dried in an oven at 50.degree. C. 
for one week to yield a final coat 5 mils thick weighing 21 mgs on each 
tablet. Finally, a 5 mil aperture was mechanically drilled through the 
composite wall to produce the osmotic device with each containing 170 mg 
of sodium acetazolamide, 8.5 mg of polyvinylpyrrolidone and 1.81 mg of 
magnesium stearate. The in vitro release rate for the devices was measured 
in a release rate machine that consisted of a series of test tubes with 
each tube containing 25 ml of distilled water at 37.degree. C. The test 
was carried out by placing the devices in the first tubes for one hour, 
then the devices were transferred to the second tubes for one hour, and 
then with matching places into the remaining tubes. The devices were 
slowly oscillated throughout the test in the tubes. The amount of 
acetazolamide released was measured spectrophotometrically at 265 m.mu. at 
low pH. The device had a controlled and continuous rate of release of 
about 18 mgs per hour over a prolonged period of 6 hours. 
EXAMPLE 10 
The procedure of Example 9 was repeated in this example with all conditions 
as described except that the wall of the device was formed essentially 
free of the stabilizer added in Example 9 to impart inertness to the wall 
in the presence of sodium acetozolamide. The composition used to form the 
wall in this example consists of 218.5 grams of cellulose acetate having 
an acetyl content of 32% and 11.5 grams of polyethylene glycol having a 
molecular weight of 400 dissolved in 5520 grams of the solvent methylene 
chloride:methanol mixed in the ratio of 80:20. The amount of sodium 
acetazolamide released was measured as previously described and the device 
had an increasing rate of release from 10 to 35 mgs over up to three hours 
and a decreasing rate of release from 35 to 8 mg from three hours up to 
six hours of release time. 
EXAMPLE 11 
A plurality of osmotic drug delivery devices are manufactured according to 
the procedure of Example 9 wherein the conditions were as described except 
that the drug of Example 9 was replaced by an orally administrable drug 
selected from the group consisting of methazolamide, ethoxyolamide, 
diazepam, amitriptylene hydrochloride, imipramine hydrochloride, niacin, 
benzthiazide, chlorothiazide, tolbutamide, tolazamide, chloropropamide, 
procainamide hydrochloride, colchicine, and atropine. 
EXAMPLE 12 
An oral osmotic device for releasing the vitamin ascorbic acid in the 
gastrointestinal tract was manufactured as follows: first, a wall forming 
composition was prepared by thoroughly blending in a high shear blender 
for 45 minutes at 22.2.degree. C. and 1 atmosphere a batch consisting of 
61% cellulose acetate having an acetyl content of 32%, 29% cellulose 
acetate having an acetyl content of 38.3% and 10% polyethylene glycol 
having a molecular weight of 400 dissolved in acetone:water solvent 
formulated on a 90:10 weight-by-weight ratio to produce a homogenous 
composite. 
Next, 200 grams of ascorbic acid was slowly added to 10 grams of 
ethylcellulose in 100 milliliters of isopropyl alcohol and the materials 
blended for 45 minutes to produce wet granules. The granules were dried at 
50.degree. C. for 48 hours and then passes through a No. 20 mesh sieve. 
Then, the granules were lubricated with 1% magnesium stearate by mixing in 
a blender and after 30 minutes of blending they were passed through a No. 
20 sieve. The granules were then pressed into a solid mass using a 
standard tableting machine and a 14.8 mm diameter punch. The compressed 
mass had a finished hardness of 7 kg as measured by a Stong-Cobb hardness 
tester. 
Next, the compressed mass and the wall forming composite were placed in a 
Wurster air suspension machine and the mass coated until each had a coat 
4.7 mils thick. An osmotic passageway 7 mils thick was drilled through the 
wall to yield the osmotic device. Each device contained 400 mgs of 
ascorbic acid and had a continuous release rate of about 30 mgs per hour 
over a period of 8 hours. 
EXAMPLE 13 
The procedure of Example 12 is repeated but ascorbic acid is replaced by 
nicotinamide, mannitol hexanitrate, isocarboxyazid, triamcinolone, 
tranylcypromine, meprobamate, malamide, salicylamide, or aspirin to give 
the corresponding osmotic device. 
EXAMPLES 14-15 
Two oral osmotic devices were manufactured following the procedure of 
Example 9. The wall of each device consisted of a composite of 40% 
cellulose acetate having a 32% acetyl content, 40% cellulose acetate 
having an acetyl content of 38.3% and 20% polyethylene glycol having a 
molecular weight of 400. The compartment of one device contained 317 mg of 
aminophylline compounded with ethylenediamine having the equivalent of 250 
mg of theophylline, 15.85 mg of poly(vinylpyrrolidone) and 3.17 mg of 
magnesium stearate. The wall of this device was 7.5 mils thick and the 
device has a rate of release of about 18 mgs per hour through an osmotic 
passageway having a diameter of 7 mils. The compartment of the other 
device contained 333.3 mg of theophylline monoethanolamine having an 
equivalency of 250 mg of theophylline, 16.67 mg of poly(vinylpyrrolidone), 
9.5 mg of pharmaceutically acceptable red No. 3 aluminum lake and 3.17 mg 
of magnesium stearate. The wall of this device was 7.5 mils thick and the 
device had a release rate of 22 mg per hour through an osmotic passageway 
having a diameter of 7 mils. 
EXAMPLE 16 
An osmotic device for releasing theophylline monoethanolamine over a six 
hour period was manufactured using the above described procedure. The wall 
of the device consisted of a composite of 22% hydroxybutyl 
methylcellulose, 43% cellulose acetate having a 32% acetyl content, 21% 
cellulose acetate having a 38.3% acetyl content, 12% polyethylene glycol 
having a molecular weight of 400 and 2% of polyoxypropylene glycol having 
a molecular weight of 950. The wall of the device was 5.7 mils thick, the 
osmotic port had a diameter of 10 mils, the compartment contained 125 mgs 
of theophylline present as monoethanolamine, and the device had a rate of 
release of 19 mgs per hour. 
EXAMPLE 17 
An osmotic device for releasing potassium chloride for a prolonged period 
of 12 hours was manufactured using the above described procedures and 
apparatus. The wall of the device comprised a composite of 26% 
hydroxybutyl methylcellulose, 59% cellulose acetate having a 38.3% acetyl 
content, 13% polyethylene glycol having a molecular weight of 400 and 2% 
polyoxypropylene glycol having a molecular weight of 950. The wall of the 
device was 6 mils thick, the osmotic port had a diameter of 10 mils and 
the compartment contained 750 mgs of potassium chloride. 
The release rate for the device was measured in a bath that consisted of a 
series of 12 tubes with each tube containing 25 ml of double distilled 
water at 37.5.degree. C. The test was carried out by placing the device in 
the first tube for one hour, then the device was transferred to the second 
tube for one hour, and then with matching places into the remaining tubes. 
The devices were slowly oscillated throughout the test in the tubes 
containing the test solution. The amount of potassium chloride delivered 
was determined by electrical conductive measurements for each tube using a 
conductivity meter calibrated with known standards. The measured rate of 
release was about 55 mgs of potassium chloride per hour over a prolonged 
period of 12 hours. 
EXAMPLE 18 
An osmotic device is manufactured by the general procedure of Example 9. 
The semipermeable wall of the device is comprised of cellulose diacetate, 
70% by weight, having an acetyl content of 38.3% and cellulose acetate 
phthalate, 30% by weight. The wall is applied with an air suspension 
machine to a drug core from a methylene dichloride:methanol, 70:30, 
weight-by-weight solvent. The passageway is drilled as described supra. 
EXAMPLE 19 
An osmotic device is fabricated according to the general procedure of 
Example 9. The semipermeable wall of the device is comprised of cellulose 
diacetate, 70% by weight, having an acetyl content of 38.3%, and a polymer 
having a carboxybenzoyloxypropyl group, mainly, 30% by weight of 
hydropropyl methylcellulose phthalate. The wall is applied to a pressed 
drug core from an air suspension machine using a methylene 
dichloride:methanol solvent (79:21), expressed as weight-by-weight. The 
passageway is drilled as described above. 
EXAMPLE 21 
The procedure of Example 20 is repeated in this example, employing 
hydroxypropyl methylcellulose phthalate having 15-30% methoxyl content, 
4-15% hydroxypropyl content, and 15-40% carboxybenzoyl content. 
EXAMPLE 22 
An osmotic device is made according to the procedures described above. The 
semipermeable wall is comprised of 70 parts of a 50:50 composition of 
cellulose diacetate having an acetyl content of 38.3% and cellulose 
diacetate having an acetyl content of 39.8%, and 30 parts by weight of 
carboxybenzoyl cellulose. The wall is applied from a methylene 
dichloride:methanol solvent, in the ratio of 75 parts by weight to 25 
parts, from an air suspension machine. The passageway is drilled as 
described. 
EXAMPLE 23 
An osmotic device is manufactured with a wall comprising 65 parts of a 
composition of 50 parts by weight of cellulose diacetate having an acetyl 
content of 38.3% and 50 parts by weight of cellulose diacetate having an 
acetyl content of 39.8%, 30 parts by weight of carboxybenzoyl cellulose 
and 5 parts by weight of polyvinyl acetate. The solvent employed comprises 
75:25, weight by weight, of methylene dichloride and methanol. An osmotic 
orifice is drilled as described. 
EXAMPLE 24 
An osmotic device is manufactured according to the procedure of Example 23 
except that polyvinyl acetate is replaced with hydroxyethylated cellulose 
with an average number of mols of ethylene oxide of from 0.5 to 2.5, 
preferably 1 to 2.2 per anhydroglucose unit. 
EXAMPLE 25 
An osmotic device is manufactured according to the procedure of Examples 23 
and 24 with the hydroxyethylated cellulose replaced by carboxymethyl 
ethylcellulose having a degree of substitution of 2.3 ethoxyl and 0.29 
carboxymethyl groups. 
EXAMPLE 26 
The procedures of Examples 23 and 25 are followed to form a semipermeable 
wall consisting essentially of cellulose diacetate having an acetyl 
content of 38.3% 70 parts by weight, hydroxybutyl methylcellulose 10 parts 
by weight, and cellulose acetate hydrogen phthalate 20 parts by weight. 
The solvent consisted essentially of 95% of methylene dichloride and 
methanol, 80 parts by weight to 20 parts by weight, and 5% of acetone and 
water in the ratio of 90 parts by weight to 10 parts by weight. An osmotic 
orifice is drilled as described above. 
EXAMPLES 27-36 
Osmotic devices for dispensing a useful agent are manufactured according to 
the above procedures with the operable semipermeable wall of the devices 
comprising the following: lightly cross-linked hydroxypropyl cellulose and 
lightly cross-linked polyvinyl alcohol; nitrocellulose and cold water 
insoluble polyvinyl alcohol; cellulose triacetate and cellulose acetate 
propionate; cellulose triacetate and benzyl cellulose having a D.S. of 
1.8; cellulose triacetate and cyanoethyl cellulose having a D.S. of 2; 
cellulose diacetate and carbamoylethyl cellulose having a D.S. of 0.5-0.7; 
cellulose diacetate and phenyl cellulose having a D.S. of 0.80; 
dinitrophenyl cellulose dinitrate and water insoluble cellulose acetate; 
ethylcellulose acetate and lightly cross-linked cellulose acetate 
phthalate; and methylcyanoethyl cellulose acetate and water insoluble 
cellulose acetate. 
The novel osmotic devices of this invention use means for the obtainment of 
precise release rates in the environment of use while simultaneously 
maintaining the integrity of the device. 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 devices 
illustrated and described can be made without departing from the spirit of 
the invention.