Osmotic device for dispensing two different medications

An osmotic device is disclosed for delivering two beneficial drugs to an environment of use. The device comprises a semipermeable wall surrounding a lumen divided into a first compartment containing a drug that is separated from a second compartment containing a different drug. An orifice through the wall communicates with the first compartment for delivering drug from the first compartment, and another orifice through the wall communicates with the second compartment for delivering drug from the second compartment. In operation, drug is dispensed separately from each compartment by fluid being imbibed through the wall into each compartment at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall against the drug in each compartment thereby producing in each compartment a solution containing drug that is dispensed through their orifices at a controlled and continuous rate over a prolonged period of time.

FIELD OF THE INVENTION 
This invention pertains to an osmotic system manufactured in the form of an 
osmotic device. More particularly, the invention relates to an osmotic 
device that houses separately and dispenses separately at least two 
different drugs for (a) obtaining the therapeutic benefits of each drug, 
or for (b) lessening the incidence of adverse effects due to the 
incompatibility of different drugs. 
BACKGROUND OF THE INVENTION 
It is frequently desirable to prescribe pharmaceutical dosage forms 
containing at least two different drugs for obtaining the pharmacological 
benefits of each drug. The coadministration of certain drugs is prescribed 
often in fixed ratios for several reasons. For example, for drugs that 
have the same therapeutic effect but act mechanistically different on the 
body, such combinations may have the added therapeutic effect of both 
agents but less side effects, or the drugs may act synergistically and 
create a larger than additive effect. Also, drug combinations are 
prescribed for treatments where each individual drug address different 
symptoms of a particular medical situation. Although, a large number of 
therapeutic combinations could be provided, often they can not be 
compounded in the same dosage form because each drug needs to be 
administered on a different schedule. The different schedule is needed 
because different biological half lives and therapeutic indices, and 
therefore each drug should be administered in separate dosage forms on a 
prescribed schedule that is specific for each drug. Thus, a drug that 
needs to be administered four times a day, should not be combined with a 
drug that should be administered once a day. These drugs are kinetically 
incompatible in a pharmaceutical dosage form. Another reason why certain 
drugs cannot be combined is they may be chemically incompatible or 
unstable in the presence of each other. This kinetic or chemical 
incompatibility can be eliminated by the novel dosage form provided by 
this invention. For example, by using the dosage form provided by this 
invention, a regimen consisting of four times a day administration of drug 
can be transformed into a once a day administration such that the drug 
previously administered four times daily can be combined with a drug 
administered once daily. In other words, both drugs can be coadministered 
to the body at delivery rates that are matched to achieve each of their 
separate therapeutic plasma combinations. Thus, in the light of the above 
presentation, it will be appreciated by those versed in the dispensing 
art, that if a delivery device is made available for housing two or more 
different drugs at controlled and continuous rates in therapeutically 
effective amounts for obtaining the benefits of each drug, such a delivery 
device would have a definite use and be a valuable contribution to the 
dispensing art. 
OBJECTS OF THE INVENTION 
Accordingly, it is an immediate object of this invention to provide an 
osmotic device that contributes to the prior art by making available an 
osmotic device that can dispense at least two different beneficial drugs 
over a prolonged period of time for obtaining the pharmacological and the 
physiological benefits of each drug. 
Another object of this invention is to provide a dosage form for separately 
housing and separately dispensing at least two drugs and which dosage form 
overcomes the problems known to the prior art. 
Yet another object of the invention is to provide an osmotic device that 
provides independent controlled and continuous delivery of two drugs to 
biological drug receptors over a prolonged period of time. 
Yet another object of the invention is to provide an osmotic device that 
can dispense separately two different drugs at controlled and continuous 
rates for performing their intended therapeutic effects. 
Still a further object of the invention is to provide an osmotic device 
that can administer independently two different drugs as a complete 
pharmaceutical regimen to a human for a particular time period, the use of 
which requires intervention only for initiation and possibly terminiation 
of the regimen. 
Yet still another object of the invention is to provide an osmotic device 
for dispensing separately two different drugs in known amounts per unit 
time. 
Yet still another object of the invention is to provide an osmotic device 
that can deliver separately two different drugs and has an economic 
advantage for the user by keeping to a minimum the number of doses 
administered and reduces missed doses because of forgetfulness. 
Other objects, features and advantages of the invention will be more 
apparent to those versed in the art from the following specification, 
taken in conjunction with the drawings and the accompanying claims.

In the drawings and the specification, like parts in related figures are 
identified by like numbers. The terms appearing earlier in the 
specification and in the description of the drawings, as well as 
embodiments thereof, are further described elsewhere in the disclosure. 
DETAILED DESCRIPTION OF THE DRAWINGS 
Turning now to the drawings in detail, which are an example of various 
osmotic delivery devices provided by the invention, and which example is 
not to be considered as limiting, one example of an osmotic device is 
indicated in FIGS. 1 to 3 and designated by the numeral 10. In FIG. 1, 
osmotic device 10 comprises a body 11 having a wall 12 that surrounds and 
forms an internal lumen divided into a first compartment 13, seen in 
dashed outline in FIG. 1, and in opened section in FIG. 2, and a second 
compartment 14 separated from adjoining compartment 13 by a partition 15. 
A first orifice 16 in wall 12 communicates with compartment 13 and the 
exterior of device 10, and a second orifice 17 communicates with 
compartment 14 and the exterior of device 10. 
Compartment 13, as seen in FIG. 2, in one embodiment contains a beneficial 
drug 18, represented by dots, that is soluble in an external fluid and 
exhibits an osmotic pressure gradient across wall 12 against the fluid. 
Compartment 13 in another embodiment contains a drug 18 that has limited 
solubility in the external fluid and exhibits a limited solubility across 
wall 12 against the fluid. In this latter embodiment, drug 18 is mixed 
with an osmagent 19, indicated by wavy lines, that is soluble in the 
external fluid and exhibits an osmotic pressure gradient across wall 12 
against the fluid. Compartment 14 contains a different drug 20 than drug 
18. Drug 20 is soluble in the external fluid and exhibits an osmotic 
pressure gradient across wall 12, or drug 20 has limited solubility in the 
fluid and exhibits a limited pressure gradient across wall 12. Drug 20 in 
this latter physical chemical state is mixed with osmagent 19 that is 
soluble in the fluid and exhibits an osmotic pressure gradient across wall 
12. Osmagent 19 can be the same or different in first compartment 13 and 
second compartment 14. 
Wall 12 of osmotic device 10, as seen in FIGS. 1 and 2, comprises a 
semipermeable wall formed of a material that is permeable to the passage 
of an external fluid and it is essentially impermeable to the passage of 
drug 18, drug 20, and osmagent 19. Wall 12 is substantially inert, it 
maintains its physical and chemical integrity during the dispensing of the 
beneficial drugs, and it is non-toxic to animals including humans. Wall 12 
of osmotic device 10, as seen in an embodiment in FIG. 3, comprises a 
laminate formed of a semipermeable lamina 12a in laminar arrangement with 
a microporous lamina 12b. Microporous lamina 12b consists of preformed 
microporores 21, or micropores formed in the environment of use. 
Microporous lamina 12b is inert and non-toxic. In FIG. 3, device 10 is 
manufactured in the embodiment illustrated with microporous lamina 12b 
facing the environment of use, and with semipermeable lamina 12a facing 
the lumen of device 10. In another embodiment, device 10 is manufactured 
with microporous lamina 12b positioned inside and with semipermeable 
lamina 12a positioned outside facing the environment of use. Both the 
semipermeable lamina and the microporous lamina can contain additional 
wall forming agents such as flux enhancers, flux reducers, plasticizers 
and the like. 
The osmotic delivery system as seen in FIGS. 1 through 3 can be made into 
many embodiments including the presently preferred embodiments for oral 
use, that is, for releasing locally or systemically acting therapeutic 
medicaments in the gastrointestinal tract over a prolonged period of time. 
The oral system can have various conventional shapes and sizes such as 
round with a diameter of 1/8 inch to 1/2 inch, or it can be shaped like a 
capsule having a range of sizes from triple zero to zero, and from 1 to 8. 
In these manufactures system 10 can be adapted for administering drug to 
numerous animals, including warm blooded mammals, avians, reptiles and 
pisces. 
While FIGS. 1 through 3 are illustrative of various delivery systems that 
can be made according to the invention, it is to be understood these 
systems are not to be considered as limiting, as the system can take a 
wide variety of shapes, sizes and designs adapted for delivering the drug 
to different biological environments of use. For example, the delivery 
system includes anal-rectal, artificial gland, blood system, buccal, 
cervical, dermal, ear, implant, intrauterine, nasal, subcutaneous, vaginal 
and the like. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the practice of this invention it has now been found an 
osmotic delivery system can be made for delivering at least two different 
drugs independently and simultaneously to a biological environment of use. 
The delivery system comprises the two compartments as seen in FIGS. 1 to 3 
discussed above, with the drugs delivered independently from each 
compartment. The system described here is made with the same membrane 
composition and thickness on each compartment. The delivery equation for 
each osmotic compartment is given by equation 1. 
##EQU1## 
wherein K is the water permeability constant for the wall, A is the area 
of exposed surface of a compartment, .DELTA..pi. is the difference between 
the osmotic pressure in a compartment compared with the external osmotic 
pressure, S.sub.D is the solubility of the drug in fluid that enters the 
compartment, and h is the thickness of the wall of the device. The ratio 
of release rates from compartment 1, the first compartment, to compartment 
2, the second compartment, is given by equation 2. 
##EQU2## 
wherein the K, A, .pi., and .sup.S D are as defined, and the wall on 
compartment 1 and compartment 2 are similar for homogenous walls, that is, 
the wall permeability K.sub.1 =K.sub.2, and the wall thickness h.sub.1 
=h.sub.2. Equation 2 reveals that the ratio of delivery of one drug from 
one compartment to another drug from the other compartment is dependent 
only on the properties of the drugs, their associated osmagents, and 
surface areas of the compartments. The relative release rate from each 
compartment is modified or changed, by changing the composition in each 
compartment, and not the composition of the wall. Alternatively, the two 
compartments can be manufactured to have separate wall compositions and or 
thicknesses such that the two rates can be engineered independently of 
each other using also the membrane properties. Such a structure can be 
achieved by coating the total system with the same membrane and 
subsequently layering a separate laminate with thickness h.sub.3 onto 
either compartment (1) or (2), as illustrated in FIG. 4, wherein h.sub.1 
is the thickness of the wall surrounding the first compartment, h.sub. 2 
is the thickness of the wall at the second compartment, and h.sub.3 is the 
thickness of the lamina added to the second compartment. Lamina h.sub.2 
can be formed of a different semipermeable material, a material 
impermeable to fluid, a material that bioerodes over time, and the like. 
The materials forming the semipermeable wall of the delivery device are 
those that do not adversely affect the drug and the osmagent, an animal 
body, or other host, is permeable to an external fluid, such as water and 
biological fluid, while remaining essentially impermeable to drug, 
osmagents, and the like. The selectivity permeable materials forming wall 
12 are insoluble in body fluids, they are nonerodible, or they can be made 
to bioerode after a predetermined period with bioerosion corresponding to 
the end of the drug release period. Typical materials for forming wall 12 
include semipermeable materials known to the art as osmosis and reverse 
osmosis polymers. The semipermeable polymers include cellulose acylate, 
cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose 
diacetate, cellulose triacetate, beta-glucan acetate, acetaldehyde 
dimethyl acetate, cellulose acetate ethyl carbamate, polyamide, 
polyurethane, sulfonated polystyrene, cellulose acetate phthalate, 
cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose 
acetate dimethylaminoacetate, cellulose acetate chloroacetate, cellulose 
dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulose 
dipentanlate, cellulose acetate valerate, cellulose acetate 
p-toluenesulfonate, cellulose acetate butyrate, ethylcellulose, 
selectively permeable polymers formed by the coprecipitation of a 
polycation and a polyanion as disclosed in U.S. Pat. Nos. 3,173,876; 
3,276,586; 3,541,005; 3,541,006 and 3,546,142. Generally, semipermeable 
materials useful for forming wall 12 will have a fluid permeability of 
10.sup.-5 to 10.sup.-1 (cc.mil/cm.sup.2.hr.atm) expressed per atmosphere 
of hydrostatic or osmotic pressure across wall 12 at the temperature of 
use. Other suitable materials are known to the art in U.S. Pat. Nos. 
3,845,770; 3,916,899; 4,036,228 and 4,111,202. 
The microporous materials comprising microporous lamina 12b maintains their 
physical and chemical integrity during the period of time drug is released 
from system 10. The microporous materials comprising lamina 12b generally 
can be described as having a sponge-like appearance that provides a 
supporting structure for microscopic sized interconnected pores or voids. 
The materials can be isotropic wherein the structure is homogenous 
throughout a cross-sectional area, the materials can be anisotropic 
wherein the structure is non-homogenous throughout a cross-sectional area, 
or the materials can have both cross-sectional areas. The materials are 
opened-celled, as the micropores are continuous or connected, with pores 
having an opening on both faces of the microporous lamina. The micropores 
are interconnected through tortuous paths of regular and irregular shapes 
including linear, curved, curved-linear, randomly oriented continuous 
pores, hindered connected pores, and other interconnected porous paths 
discernable by microporous examination. 
Generally, the microporous lamina are characterized as having a reduced 
bulk density as compared to the bulk density of the corresponding 
non-porous microporous lamina. The morphological structure of the total 
microporous wall have a greater proportion of total surface area than the 
non-porous wall. The microporous wall can be further characterized by the 
pores size, the number of pores, the tortuosity of the microporous paths, 
and the porosity which relates to the size and the number of pores. 
Generally, material possessing from 5% to 95% pores, and having a pore 
size of from 10 angstroms to 100 microns can be used for making wall 12. 
Materials useful for making the microporous lamina include polycarbonates 
comprised of linear polyesters of carbonic acid in which carbonate groups 
recur in the polymer chain, microporous materials prepared by the 
phosgenation of a dihydroxyl aromatic such as bisphenol, a microporous 
poly(vinylchloride), microporous polyamides such as polyhexamethylene 
adipamide, microporous modacrylic copolymers including those formed from 
poly(vinylchloride) and acrylonitrile, microporous styrene-acrylic and its 
copolymers, porous polysulfones characterized by diphenylene sulfone in a 
linear chain thereof, halogenated poly(vinylidene), polychloroethers, 
acetal polymers, polyesters prepared by esterification of a dicarboxylic 
acid or anhydride with an alkylene polyol, poly(alkylenesulfides), 
phenolics, polyesters, microporous polysaccharides having substituted 
anhydroglucose units exhibiting a decrease permeability to the passage of 
water and biological fluids, asymmetric porous polymers, cross-linked 
olefin polymers, hydrophobic or hydrophilic microporous homopolymers, 
copolymers or interpolymers having a reduced bulk density, and materials 
described in U.S. Pat. Nos. 3,595,752; 3,643,178; 3,654,066; 3,709,774; 
3,718,532; 3,803,601; 3,852,224; 3,852,388; and 3,853,601; in British Pat. 
No. 1,126,849; and In Chem. Abst. Vol. 71, 427F, 22573F, 1969. 
Additional microporous materials for forming microporous lamina 12b include 
poly(urethane), cross-linked chain-extended poly(urethane), poly(imides), 
poly(benzimidazoles), collodion, regenerated proteins, semi-solid 
cross-linked poly(vinyl-pyrrolidone), microporous materials prepared by 
diffusion or multivalent cations into polyelectrolyte sols, microporous 
derivatives of poly(styrene) such as poly(sodium-styrene-sulfonate), 
poly(vinyl benzyl trimethyl-ammonium chloride), microporous cellulosic 
acylates and the like microporous polymers are known in U.S. Pat. Nos. 
3,524,753; 3,565,259; 3,276,589; 3,541,055; 3,541,006; 3,546,142; 
3,615,024; 3,646,178; and 3,852,224. 
The pore-formers useful for forming the microporous lamina in the 
environment of use include solids and pore-forming liquids. The term 
pore-former as used herein also embraces micropath formers, and removal of 
the pore and/or pore-former leads to both embodiments. In the expression 
pore-forming liquids, the term for this invention generically embraces 
semi-solids and viscous fluids. The pore-formers can be inorganic or 
organic and the lamina forming polymer usually contains from 5 to 70% by 
weight of the pore-former, and more preferably about 20 to 50% by weight. 
The term pore-former for both solids and liquids include substances that 
can be dissolved, extracted or leached from the precursor microporous wall 
by fluid present in the environment of use to form operable, open-celled 
type microporous lamina. The pore-forming solids have a size of about 0.1 
to 200 microns and they include alkali metal salts such as lithium 
carbonate, sodium chloride, sodium bromide, potassium chloride, potassium 
sulfate, potassium phosphate, sodium acetate, sodium citrate, and the 
like. Organic compounds such as saccharides including the sugars sucrose, 
glucose, fructose, mannitol, mannose, galactose, sorbitol and the like. 
They can be polymers soluble in the environment of use such as 
Carbowaxes.RTM., Carbopol.RTM., and the like. The pore-formers embrace 
diols, polyols, polyhydric alcohols, polyalkylene glycols, polyglycols, 
poly(.alpha.-.omega.)-alkylenediols, and the like. The pore-formers are 
non-toxic and on their removal from lamina 12b, channels and pores are 
formed through the lamina that fill with fluid present in the environment 
of use. 
The partition between the first and second compartments is formed of a 
semipermeable, microporous, or impermeable polymer, which partition is 
impermeable to the passage of drug and osmagents. The impermeable polymer 
additionally is impermeable to the passage of fluid. The materials used 
for forming semipermeable and microporous partition are the above 
materials. Materials used for forming impermeable partitions include high 
density polyethylene and polypropylene, polyethylene terephthalate, 
aluminum foil coated with polyethylene, inert organic and inorganic 
materials, and the like. The partition can be formed of composites such as 
inorganic material added to a polymer, for example calcium phosphate added 
to cellulose acetate to form an inactive partition. In addition, the 
partition materials can be granulated such that it is pressed onto the 
first compartment, then the second compartment is pressed onto the 
partition using a standard layer tablet press. Generally, the partition 15 
will have a thickness of about 2 to 10 mils and will function to maintain 
the integrity of the first and second compartments. 
The expression orifice as used herein comprises means and methods suitable 
for releasing the drug from each compartment. The orifice will pass 
through the semipermeable wall, or through the semipermeable-microporous 
laminated wall for communicating each compartment with the exterior of the 
device. The expression includes passageway, or bore through wall formed by 
mechanical procedures or by eroding an erodible element, such as a gelatin 
plug in the environment of use. Generally, the orifice will have a 
diameter of 1 mil to 15 mils in the wall or laminate. A detailed 
description of osmotic orifices and the maximum and minimum dimensions for 
an orifice are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899. 
The osmagents, or osmotically effective compounds that can be used in the 
first compartment or in the second compartment include organic and 
inorganic compounds or solutes that exhibit an osmotic pressure gradient 
across the semipermeable wall against an external fluid. Osmagents, or 
osmotically effective compounds include magnesium sulfate, magnesium 
chloride, sodium chloride, lithium chloride, potassium sulfate, potassium 
acid phosphate, mannitol, urea, sucrose, and the like. Osmagents are known 
to the art in U.S. Pat. Nos. 3,854,770; 4,077,407; and 4,235,236. 
The term drug as used in the specification and the accompanying claims 
includes physiologically or pharmacologically active substances that 
produce a localized or systemic effect or effects in animals, avians, 
pisces and reptiles. 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, sedatives, psychic 
energizers, tranquilizers, anticonvulsants, muscle relaxants, 
antiparkinson agents, analgesics, anti-inflammatory, local anesthetics, 
muscle contractants, anti-microbials, anti-malarials, hormonal agents, 
contraceptives, sympathomimetics, diuretics, anti-parasites, neoplastics, 
hypoglycemics, nutritional agents, ophthalmic, electrolytes, and the like. 
The drug housed and delivered from each compartment in a presently 
preferred embodiment embraces a different drug in the first compartment 
and in the second compartment respectively as represented by the 
following: anti-inflammatory and anti-pyretic, anti-inflammatory and 
analgesic, bronchodilator and vasodilator, beta-blocker and diuretic, 
beta-blocker and beta-blocker, beta-blocker and vasodilator, beta-agonist 
and muscle relaxant, beta-adrenergic agonist and histamine receptor 
antagonist, anti-histamine and decongestant, beta-adrenergic stimulator 
and muscle relaxant, anti-hypertensive and diuretic, analgesic and 
analgesic, antisposmatic and anticholenergic, tranquilizer and 
anticholenergic, anticholenergic and histamine receptor antagonist, and 
the like. 
Exemplary drugs that can be in the first compartment and the second 
compartment include prenalterol in the first compartment and hydralazine 
in the second compartment as used in chronic congestive heart failure in 
short and long term therapy, propranolol in the first compartment and 
hydralazine in the second compartment for the management of hypertension, 
acetophenetidin in one compartment and aspirin in the other compartment 
for analgesic and anti-inflammatory therapy, phenacetin in one compartment 
and ethoxyacetanilide in the other compartment for antipyretic and 
analgesic therapy, magnesium trisilicate in one compartment and aspirin in 
the other compartment as an analgesic antacid therapy, cyptenamine tannate 
in one compartment and methylclothiazide in the other compartment for 
treating hypertension, meprobamate in one compartment and pentaerythritol 
tetranitrate used as prophylaxis in the management of angina pectoris, and 
in the first and second compartment theophylline and ephedrine for 
treating ambulatory asthmatics, theophylline and albuterol, ketolifen and 
theophylline, spironolactone and hydrochlorothiazide, chlorothalidone and 
spironolactone, and the like. The amount of drug in each compartment 
generally is from 0.05 ng to 1000 mg, with different devices having 
individual compartments containing 1 mg, 5 mg, 100 mg, 250 mg, and the 
like. The beneficial drugs are known to the art in Pharmaceutical 
Sciences, by Remington, 14th Ed., 1970 published by Mack Publishing Co., 
Easton, PA; and in American Drug Index, 1976, published by J. B. 
Lippincott Co., Philadelphia, PA. 
The drug present in the compartments of the device can be in various forms, 
such as uncharged molecules, molecular complexes, pro-drug, 
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 salts 
can be used. Derivatives of drugs such as esters, ethers and amides, which 
have solubility characteristics suitable for use herein can be used. The 
expression drug formulation as used herein generically includes the drug, 
or the drug in the various forms, in either embodiment mixed with a 
non-toxic osmagent in the first or in the second compartment. The drug can 
be in the compartment as a suspension, dispersion, paste, cream, particle, 
granule, emulsion, powder, and the like. 
The osmotic device of the invention is manufactured by standard techniques. 
For example, in one manufacture, a drug and optionally an osmagent and 
other ingredients that may be housed in one compartment are mixed into a 
solid, semi-solid, moist, or pressed state by conventional methods such as 
ballmilling, calendering, stirring or roll-milling, and then pressed into 
a preselected shape. A partition is formed by molding, spraying, pressing, 
or dipping one surface of the pressed shape into the partition forming 
material. The second compartment is formed by pressing a drug, or 
optionally a drug and an osmagent into a preselected shape that 
corresponds to the above formed shape, and then intimately attaching it to 
the partition, or a drug and an osmagent can be pressed directly onto the 
partition. Finally, the two compartments are surrounded with a 
semipermeable wall, or they are surrounded by a laminated wall. 
Optionally, system 10 can be manufactured by first fabricating one 
compartment by pressing in a standard tableting machine a drug to form a 
predetermined shaped compartment which is then surrounded by a wall 
forming material to form a closed compartment. Next, the other compartment 
is formed by pressing drug to first compartment. Finally, the two adjacent 
compartments are surrounded with a wall formed of a semipermeable 
material, and a passageway is drilled through the wall into each 
compartment to form system 10 with two distinct compartments and two 
distinct orifices for dispensing two drugs from system 10. 
The compartments, as described immediately above can be joined by methods 
well-known to the art, or they can be integrally formed as illustrated in 
the above figures. One operable method for joining the compartments 
consists in applying a dash or thin layer of a non-toxic adhesive to the 
joinable surfaces immediately preceeding their alignment into a working 
structure. Adhesives suitable for the present purpose include 
semipermeable silicon glue, cellulose nitrate, cellulose acetate, vinyl 
acetate and vinyl chloride adhesives, acrylic resins, aldehyde resins, 
water soluble gums, aqueous dispersions of paraffins, monomeric esters of 
.alpha.-cyanoacrylic acid, ureas, and the like. These adhesives are 
disclosed to the art in U.S. Pat. Nos. 3,547,771; 3,552,994; 3,598,781; 
3,627,559; 3,627,609; 3,755,044; and 3,759,264; in West Germany Pat. No. 
DT2,009,968; and in British Pat. No. 577,735. The compartments also can be 
joined by other methods including heat sealing, pressing, consecutively 
casting the compartments in a dual cavity mold, overlaying, and the like. 
The walls, lamina and partition forming the system can be joined by various 
techniques such as high frequency electronic sealing that provides clean 
edges and firmly formed walls, lamina and partitions, and, a presently 
preferred technique that can be used is the air suspension procedure. This 
procedure consists in suspending and tumbling the drug or osmagent in a 
current of air and a wall forming, or lamina forming, composition until 
the wall or lamina is applied to the drug. The air suspension procedure is 
well-suited for independently forming the walls and lamina. The air 
suspension procedure is described in U.S. Pat. No. 2,799,241; in J. Am. 
Pharm. Assoc., Vol. 48, pages 451 to 459, 1959; and ibid., Vol. 49, pages 
82 to 84, 1960. Other wall and laminating techniques such as pan coating 
can be used in which the materials are deposited by successive spraying of 
the polymer solution on the drug accompanied by tumbling in a rotating 
pan. Other standard manufacturing procedures are described in Modern 
Plastics Encyclopedia, Vol. 46, pages 62 to 70, 1969; and in 
Pharmaceutical Sciences, by Remington, 14th Ed., pages 1626 to 1678, 1970, 
published by Mack Publishing Company, Easton, Pa. 
The microporous lamina, in optional manufacturing embodiments, can be 
manufactured with microporous wall forming polymers that are commercially 
available, or they can be made by art known methods. The microporous 
materials can be made and then manufactured into a device by etched 
nuclear tracking, by cooling a solution of flowable polymer below its 
freezing poing whereby solvent evaporates from the solution in the form of 
crystals dispersed in the polymer, and then curing the polymer followed by 
removing the solvent crystals, by cold or hot stretching of a polymer at 
low or high temperatures until pores are formed, by leaching from a 
polymer soluble pore forming component by use of an appropriate solvent, 
and by dissolving or leaching a pore former from the wall of a device in 
operation in the environment of use. Processes for preparing microporous 
materials are described in Synthetic Polymer Membranes, by R. E. Kesting, 
Chapters 4 and 5, 1971, published by McGraw Hill, Inc; Chemical Reviews, 
Ultrafiltration, Vol. 18, pages 373 to 455, 1934; Polymer Eng. and Sci., 
Vol. 11, No. 4, pages 284 to 288, 1971; J. Appl. Poly. Sci., Vol. 15, 
pages 811 to 829, 1971; and in U.S. Pat. Nos. 3,565,259; 3,615,024; 
3,751,536; 3,801,692; 3,852,224; and 3,849,528. 
Generally, the semipermeable wall will have a thickness of 2 to 20 mils, 
with a presently preferred thickness of 4 to 12 mils. The partition 
between the compartment generally will have a thickness of 1 mil to 7 
mils, with a presently preferred thickness of 2 to 5 mils. In laminated 
walls, the lamina will have a thickness of 2 to 10 mils with a presently 
preferred thickness of 2 to 5 mils. Of course, thinner and thicker walls, 
lamina and partitions for use with numerous drugs and osmagents are within 
the scope of the invention. 
Exemplary solvents suitable for manufacturing the wall and the lamina 
include inert inorganic and organic solvents that do not adversely harm 
the wall and lamina materials, and the final system. The solvents broadly 
include members selected from the group consisting of aqueous solvents, 
alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated 
solvents, cycloaliphatic aromatics, heterocyclic solvents and mixtures 
thereof. Typical solvents include acetone, diacetone alcohol, methanol, 
ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, 
isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl 
acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, 
n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol 
monoethyl acetate, methylene dichloride, ethylene dichloride, propylene 
dichloride, carbon tetrachloride, nitroethane, nitropropane, 
tetrachloroethane, ethyl ether, isopropyl ether, cyclo-hexane, 
cyclo-octane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, 
diglyme, water, and mixtures thereof such as acetone and water, acetone 
and methanol, acetone and ethyl alcohol, methylene dichloride and 
methanol, and ethylene dichloride and methanol, and mixtures thereof. 
DESCRIPTION OF EXAMPLES OF THE INVENTION 
The following examples are merely illustrative of the present invention and 
they should not be considered as limiting the scope of the invention in 
any way, as these examples and other equivalents thereof will become 
apparent to those versed in the art in the light of the present 
disclosure, the drawings and the accompanying claims. 
EXAMPLE 1 
An osmotic delivery device for the controlled and continuous delivery of 
the two beneficial drugs hydralazine and metoprolol to a biological 
environment of use is manufactured as follows: first, a reservoir forming 
composition for housing in one compartment is compounded from 50 mg of 
hydralazine hydrochloride, 208 mg of mannitol, 8 mg of 
hydroxypropylmethylcellulose and 8 mg of stearic acid by mixing the 
hydralazine hydrochloride and the mannitol and then passing the mixture 
through a 40-mesh screen, next, the hydroxypropyl methylcellulose is 
dissolved in a 70/30 (w/w/%) ethanol-water solution and the 
hydralazine-mannitol mixture is added to the wet hydroxypropyl 
methylcellulose and all the ingredients blended for 10 minutes. Next, the 
blend is passed through a 10-mesh screen and spread on a tray and dried in 
an oven at 50.degree. C. for 18-24 hours. The dried blend is passed 
through a 20-mesh screen, placed in a mixer, and the stearic acid added to 
the blend and the mixing continued for 10 minutes. 
A second reservoir forming composition comprising 190 mg of metoprolol 
fumarate, 10 mg of polyvinyl pyrrolidone, and 3 mg of magnesium stearate 
is made by first passing the metoprolol fumarate through a 40-mesh screen, 
next, the polyvinyl pyrrolidone is dissolved in a 70/30 (w/w/%) 
ethanol-water solution, the metoprolol fumarate is placed in a mixer and 
the wet polyvinyl pyrrolidone added thereto. The ingredients are mixed for 
10 minutes, passed through a 10-mesh screen and dried in an oven at 
50.degree. C. for 24 hours. Next, the dried blend is passed through a 
20-mesh screen, placed in a mixer and the magnesium stearate added and the 
ingredients again blended to yield the reservoir composition. 
A compartment containing 274 mg of the hydralazine hydrochloride drug 
formulation as described above is prepared by placing the formulation in a 
7/16 inch convex round die and the turret of the compression machine 
turned until the load reaches the compression point with the formulation 
compressed into the shape of the die. The turret is reversed back to the 
loading position and 100 mg of solid cellulose acetate is spread over the 
compressed hydralazine formulation to form a partition. Next, another 
compartment consisting essentially of 200 mg of the metoprolol fumarate 
formulation as described above, is prepared by adding the formulation to 
the die in contact with the partition, and the formulation pressed against 
the partition. The two united compartments were then coated in a 
suspension-coating machine with a wall of semipermeable cellulose acetate 
from a wall forming composition comprising 85% cellulose acetate having an 
acetyl composition of 36%, and 15% hydroxypropyl methylcellulose dissolved 
in an 80 to 20 parts by weight of a methylene chloride-methanol solvent. 
The two compartments are coated with the cellulose acetate solution to 
form a semipermeable wall having a thickness of 6 mils. The coated 
compartments are dried in a forced air oven at 50.degree. C. for one week, 
and an orifice is laser drilled through the wall into one compartment, and 
then an orifice is drilled through the wall communicating with the other 
compartment. The orifices have a diameter of 10 mils for delivering each 
drug from the device. The osmotic system has a release rate of 2 mg/hr for 
hydralazine hydrochloride and 13 mg/hr for metoprolol fumarate. 
EXAMPLE 2 
An osmotic therapeutic system manufactured in the form of an oral, osmotic 
device for delivering two drugs to the gastrointestional tract is 
manufactured as follows: first, 275 mg of a drug formulation consisting 
essentially of 18.2% hydrazaline hydrochloride, 75.9% mannitol, 2.9% 
hydroxypropylmethyl cellulose and 3% stearic acid is pressed into a solid 
mass in a commercially available Manesty tableting machine to a Stoke's 
hardness of 8 kp. Next, a drop of liquid cellulose acetate is spread onto 
one surface of the pressed formulation. Then, 203 mg of a drug formulation 
consisting essentially of 93.5% metoprolol fumarate, 5% polyvinyl 
pyrrolidone and 1.5% magnesium stearate is placed in the Manesty press on 
top of the cellulose acetate that forms a partition separating the two 
different drug formulations. Next, the formulation is pressed to a Stoke's 
hardness of 8 kp. The two united drug formulations are then coated in an 
air suspension machine, first with an interior lamina consisting of 65% 
cellulose acetate having an acetyl content of 36% and 35% hydroxypropyl 
methylcellulose to a thickness of 3.9 mil from a methylene 
chloride-methanol solvent, and then with an exterior lamina consisting 
essentially of 85% cellulose acetate and 15% hydroxypropyl methyl 
cellulose forming a 1 mil thick lamina from a methylene chloride-methanol 
solvent. The osmotic device is dried in a forced oven at 50.degree. C. 
for 120 hours and a 10 mil osmotic orifice is drilled through the laminate 
facing the hydrazaline compartment and another 10 mil osmotic orifice is 
drilled through the laminate facing the metoprol compartment. 
EXAMPLE 3 
The procedures of Examples 1 and 2 are followed for producing delivery 
devices housing separately in the compartments salbutamol and 
theophylline, chlordiazepoxide hydrochloride and clidinium bromide, 
acetaminophen and oxycodone, pindolol and thiazide, cimetidine and 
salbutamol, burimamide and pirenzepine, cimetidine and propantheline, 
cimetidine and isopropamide, and the like. 
EXAMPLE 4 
The procedures of Example 1 and 2 are followed for producing an oral 
osmotic delivery device comprising in the first compartment 7.3% (total 
core weight basis) hydralazine hydrochloride, 30.6% mannitol, and in the 
second compartment 42.6% oxprenolol sebacinate and 14.1% sodium 
bicarbonate. The partition between the first compartment and the second 
compartment consists essentially of 5.4% hydroxypropyl cellulose, and the 
wall of the device consists of 40% cellulose acetate having an acetyl 
content of 32%, cellulose acetate having an acetyl content of 39.8% and 
18% hydroxypropyl methylcellulose. Accompanying FIG. 5 depicts the release 
rate in mg/hr of hydralazine hydrochloride from this device, FIG. 6 
depicts the cumulative amount of hydralazine hydrochloride released over 
time, FIG. 7 depicts the release rate in mg/hr of oxprenolol sebacinate 
and FIG. 8 depicts the cumulative amount released over time from the 
device. 
The novel osmotic systems of this invention are means for the obtainment of 
precise release rates in theenvironment of use while simultaneously 
maintaining the integrity and character of the osmotic system and the 
drugs. 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 system illustrated and described can be made without 
departing from the spirit of the invention.