System for dispersing drug in biological environment

A delivery system is disclosed comprising a wall surrounding a lumen containing a plurality of dosage delivery devices. The wall is formed of an environment sensitive material that releases the dosage forms into the environment. The dosage forms comprise a semipermeable wall surrounding a compartment containing drug. A passageway through the semipermeable wall releases drug from the dosage form to the environment.

FIELD OF THE INVENTION 
This invention pertains to both a novel and unique delivery system. More 
particularly, the invention relates to a delivery system comprising an 
exterior wall that surrounds a lumen housing a plurality of dispensable 
dosage forms. The exterior wall is formed of an environment sensitive 
material that releases the dosage forms into the environment. The dosage 
forms comprise a wall that surrounds a compartment containing a drug with 
a passageway in the wall for delivering the drug over time. The dosage 
form is useful for delivering a single drug, two drugs or more, that are 
separately housed and separately dispensed for (a) obtaining the 
therapeutic benefits of each drug, (b) lessening the incidence of adverse 
effects due to the incompatability of different drugs, (c) delivering at 
least two drugs that are difficult to deliver from a dispensing system, or 
(d) dispersing a drug in a preselected area of the gastrointestinal tract. 
BACKGROUND OF THE INVENTION 
Since the beginning of antiquity, both pharmacy and medicine have sought a 
dosage from for administering a beneficial drug. The first written 
reference to a dosage form is in the Eber Papyrus, written about 1552 B.C. 
The Eber Papyrus mentions dosage forms such as anal suppositories, vaginal 
pessaries, ointments, oral pill formulations, and other dosage 
preparations. About 2500 years passed without any advance in dosage form 
development, when the Arab physician Rhazes, 865-925 A.D., invented the 
coated pill. About a century later the Persian Avicenna, 980-1037 A.D., 
coated pills with gold or silver for increasing patient acceptability and 
for enhancing the effectiveness of the drug. Also around this time, the 
first tablet was described in Arabian manuscripts written by al-Zahrawi, 
936-11009 A.D. The manuscripts described a tablet formed from the hollow 
impressions in two facing tablet molds. Pharmacy and medicine waited about 
800 years for the next innovation in dosage forms, when in 1883 Mothes 
invented the capsule for administering drug. The next quantum leap in 
dosage forms came in 1972 with the invention of the osmotic dosage form by 
inventors Theeuwes and Higuchi. The osmotic dosage form is manufactured in 
one embodiment for oral use, and in this embodiment it embraces the 
appearance of a tablet with a drug delivery portal. It is the first oral 
dosage form that delivers a given amount of drug per unit time at a rate 
controlled by the dosage form over a prolonged period of time. 
Also, since the beginning of antiquity, pharmacy and medicine sought a 
primary dosage form comprising a plurality of secondary dosage form that 
are released by the primary dosage form in a preselected region of the 
gastrointestinal tract, such as the stomach. A primary dosage form is 
needed for dispersing a plurality of secondary dosage forms in the stomach 
for their subsequent passage over time into the intestine and colon for 
administering a local or systemic therapy in the intestine and/or colon. A 
primary dosage form that immediately releases and diperses the secondary 
dosage form throughout the stomach, for their eventual passage from the 
stomach through the pylorus over a prolong period of time is achieved by 
physiologically maintaining the stomach in a feed mode. The secondary 
dosage unit cooperate over time the passage of the secondary dosage form 
for administration of drug in the intestine and/or colon. 
It is desirable to prescribe pharmaceutical dosage forms containing at 
least two different drugs for obtaining the pharmacological benefits of 
each drug. The co-administration 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 drugs but 
less side effects, or the drugs may act synergistically and create a 
larger than additive effect. 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 each drug has a 
different biological half life and therapeutic index 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 co-administered 
to the body at delivery rates that are matched to achieve each of their 
separate therapeutic plasma concentrations. 
In the light of the above presentation, it will be appreciated by those 
versed in the dispensing art, that an improved delivery system comprising 
a primary delivery member that dispenses a plurality of secondary delivery 
members in the stomach followed by their timed-passage into the intestine 
and colon for administering a drug therein, such a delivery system would 
have definite use and be a valuable contribution to the dispensing arts. 
It will also be appreciate that a novel delivery system housing a drug, or 
two, or more different drugs for independent or for simultaneous 
independent co-delivery, at continuous and controlled rates in 
therapeutically effective amounts for obtaining the benefits of each drug, 
such a delivery system would have a definite use and be a valuable 
contribution to the dispensing arts. The present invention additionally 
advances the state of the dispensing art by making available a primary 
delivery system housing a number of independent delivery portal 
pre-manufactured or formed during use for increasing the bio-availability 
of the drug, the administration of the drug in a drug receiving 
environment and concomitantly decreasing the likelihood of local unwanted 
effects, and for dispensing at least one drug, or at least two different 
drugs to a biological receptor substantially free of interaction and drug 
incompatibility. 
OBJECTS OF THE INVENTION 
Accordingly, in view of the above presentation it is an immediate object of 
this invention to provide both a novel and useful drug delivery system 
that makes a substantial contribution to the art by providing a delivery 
system useful for obtaining better therapy in the management of health and 
disease. 
Another object of the invention is to provide a delivery system that 
further perfects drug delivery by having the combined effects of 
dispersing delivered drug in the biological environment for improving its 
availability, its absorption and for minimizing local irritation of the 
biological drug receiving environment. 
Another object of the invention is to provide a delivery system for 
administering a drug in the gastrointestinal tract with a system that is 
relatively economical in cost to manufacture, provides the clinician with 
a dependable delivery system, and is well-adapted for practical and 
acceptable patient use. 
Another object of the invention is to provide a primary delivery system for 
releasing a plurality of secondary dosage forms in the gastrointestinal 
tract which dosage forms are manufactured as miniature osmotic drug 
delivery devices that diffuse and spread a delivered drug over a larger 
area of the gastrointestinal tract such as the intestine or colon. 
Another object of this invention is to provide a delivery system comprising 
a multiplicity of tiny oral, osmotic drug delivery devices that are simple 
in construction and exhibit all the practical benefits of controlled and 
continuous administration of drug during their residency in the stomach 
and/or the intestine for executing a therapeutical program. 
Another object of the invention is to provide a delivery system comprising 
(1) a plurality of tiny osmotic delivery devices, and (2) a wall 
surrounding a lumen housing the plurality of osmotic devices, the wall 
formed of (a) a material that releases the tiny devices into an 
environment having pH of 1.0 to 3.5 inclusive, or (b) a material that 
maintains its physical and chemical integrity in an environment having a 
pH of 1.0 to 3.5 inclusive, and releases the tiny devices in an 
environment having a pH of greater than 3.5 to 8.0. 
Another object of this invention to provide a delivery system that 
contributes to the dispensing art by making available a system that can 
dispense at least two different drugs at controlled rates for obtaining 
the pharmacological and physiological benefit of each drug, and which 
system thusly represents an improvement and an advancement in the delivery 
arts. 
Another object of the invention is to provide a delivery system housing 
osmotic dosage form devices for separately housing and separately 
dispensing two drugs essentially-free of chemical interactions attributed 
to chemical incompatibility, thereby overcoming the problems associated 
with the prior art. Another object of the invention is to provide a 
delivery system comprising osmotic dosage form devices embracing different 
structures and different sizes for dispensing a drug to selected loci of 
the gastrointestinal tract over time. 
Another object of the invention is to provide both a novel and useful 
primary delivery system as a means for providing a plurality of tiny 
dosage forms for dispersion in the stomach that are kept in the stomach by 
maintaining the stomach in the fed mode for extended residency for making 
them available therein for their subsequent passage into the intestine. 
Another object of the invention is to provide a means for executing a 
therapeutic program, which means comprises a primary delivery system that 
releases a plurality of dosage forms in the stomach that are kept in the 
stomach by keeping the stomach in a fed mode thereby enabling the release 
of the dosage forms from the stomach over time. 
Another object of the invention is to provide a plurality of enteric-coated 
tiny osmotic dosage forms for delivering a drug in the intestine. 
These objects, as well as other objects, features and advantages of the 
invention, will become more apparent from the following detailed 
description of the invention, 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 drawings are an example of the 
delivery system and the manufacturing procedure provided by the invention, 
and which examples are not to be construed as limiting, one example of the 
delivery system and the manufacturing procedure is seen in FIGS. 1 through 
6, considered together. 
FIGS. 1a and 1b illustrate one manufacturing step in the assembly leading 
to a delivery dosage system provided by the invention. FIGS. 1a and 1b 
depict in opened section a body portion 10 comprising a wall 11 
surrounding an internal lumen 12. Wall 11 is formed of (a) a material that 
immediately releases the contents of the delivery system, when the system 
enters an environment having a pH of 1.0 to 3.5 inclusive, or (b) a 
material that maintains its physical and chemical integrity in an 
environment having pH of 1.0 to 3.5 inclusive, but releases the contents 
of the delivery system when it enters an environment having a pH of 
greater than 3.5 to 8.0. Wall 11 surrounds and forms internal lumen 12 and 
in the embodiment illustrated in FIGS. 1a and 1b it is made as the 
receiving portion shaped like a capsule. Internal lumen 12 is receiving a 
multiplicity of tiny dosage forms 13, from hopper 14. Hopper 14 feeds a 
predetermined number of tiny dosage forms 13 into lumen 12. Wall 11 that 
surrounds and forms internal lumen 12 is a primary delivery system housing 
a plurality of secondary dosage forms 13. The secondary dosage forms 13, 
in a preferred embodiments are osmotic dosage forms for administering a 
drug in the gastrointestinal environment of use. 
FIGS. 2a and 2b illustrate another step in the manufacture of the delivery 
system 10. In FIGS. 2a and 2b body portion 10 is telescopically capped 
with an engaging cap 15 portion by a capping hopper 16 to yield the 
primary dosage system 17 as seen in FIGS. 3a and 3b. 
FIG. 4 illustrates primary delivery system 17 of FIG. 3a comprising an 
additional outer wall 18. Outer wall 18 is formed of a delayed release 
material that keeps its integrity in an environment having a pH of 1.0 to 
3.5 inclusive, but releases secondary delivery devices 13 housed therein 
when the primary delivery system 17 passes into an environment having a pH 
greater than 3.5 to 8.0. Outer wall 18 is an embodiment that can be used 
when inner wall 11 is made from a material that would release the delivery 
devices in an environment having a pH of 1.0 to 3.5 inclusive, and it is 
desired to delay their release until the delivery system enters an 
environment having a pH of 3.5 to 8.0. 
FIGS. 5 and 6 illustrate secondary dosage forms 13 manufactured as an 
osmotic delivery device 13 sized and shaped for housing in primary 
delivery system 17. Delivery device 13 of FIG. 5 is seen in opened section 
in FIG. 6. Delivery device 13 comprises a wall 20 comprising in at least a 
part, or totally, a semipermeable composition that surrounds and defines 
an internal compartment 21. Semipermeable wall 20 is permeable to the 
passage of an external fluid present in the environment of use and it is 
substantially impermeable to the passage of drug and osmotically effective 
compounds known as osmagents. Compartment 21 contains a drug 22 that is 
soluble in fluid imbibed into compartment 21 and it exhibits an osmotic 
pressure gradient across semipermeable wall 20 against an external fluid. 
In another embodiment, compartment 21 contains a drug 22 that has limited 
solubility in fluid that enters compartment 21 and is mixed with an 
osmotically effective compound that is soluble in fluid 23 imbibed into 
compartment 21 and exhibits and osmotic pressure gradient across wall 20 
against an external fluid. 
An exit means 24 is present in wall 20 that communicates compartment 21 
with the exterior of device 13 for delivering drug 22 at a controlled and 
continuous rate over a prolonged period of time. The expression exit means 
24 embraces at least one passageway or orifice that passes through wall 
20. The exit means includes also bore, pore, porous element through which 
a drug can migrate, a hollow fiber, capillary tube, and the like. The 
expression also includes a material that erodes or is leached from wall 20 
in a fluid environment of use to produce at least one passageway in the 
secondary dosage form 13. Representative materials suitable for forming at 
least one passageway, or a multiplicity of passageways include an erodible 
poly(glycol) or poly(lactic) acid member in the wall, a gelatinous 
filament, poly(vinylalcohol), leachable materials such as fluid removable 
pore forming salts, oxide, polysaccharides and the like. A passageway can 
be formed by leaching a material such as sorbitol from the wall. The 
passageway can be formed by wall 20 bursting to form a passageway of 
controlled dimensions in operation of secondary dosage form 13. The 
passageways can have any shape, such as round, elliptical and the like. 
The device can be constructed with one or more passageways in a spaced 
apart relation on more than a single surface of the dosage form. 
Passageways and equipment for forming passageways are disclosed in U.S. 
Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and 4,088,864. Passageways 
formed by leaching are disclosed in U.S. Pat. No. 4,200,098. Passageways 
formed by osmotic bursting pressure are disclosed in U.S. Pat. No. 
4,016,880. 
Dosage 13 can be formed in an embodiment, optionally with an internal 
partition 25. Partition 25 comprises an expandable material to define an 
expansion compartment 27. Compartment 27 contains an expandable member 26 
that is (a) an osmagents or (b) an osmopolymer. In either embodiments, the 
osmagents, or the osmopolymer imbibes and absorbs fluid from the 
environment of use causing compartment 27 to (c) fill with solution 
containing osmagent, or to (d) fill with an expanding osmopolymer, thereby 
urging in (c) or (d) partition 25 to expand and assist compartment 21 in 
dispensing drug 22 through passageway 24 from device 13. In a preferred 
embodiment, when compartment 27 comprises an osmopolymer, dosage form 13 
is manufactured without partition 25. In this manufacture, osmopolymer 26 
expands into compartment 21 directly against drug layer 22 thereby pushing 
drug 22 through passageway 24 of dosage form 13. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the practice of this invention, delivery system 17 
comprising a wall 11 that surrounds an internal lumen 12 can in one 
embodiment be made as a capsule. The capsules are made of tasteless 
materials, they are easily filled and they are easily self-administered by 
a patient in readily assimilable form. The capsules are conveniently made 
in two parts, with one part slipping over the other part for completely 
surrounding delivery device 13 housed therein. The capsules can have a 
variety of sizes from triple zero to five. The capsules used for the 
purpose of the invention can be transparent and colorless, or colored 
capsules can be used to give a special product a distinctive appearance. 
The capsules can be filled with the drug delivery devices by manual or 
machine filling methods. 
The materials useful for forming wall 11 of delivery system 17 that 
instantly release delivery device 13 in an environment having a pH of 1.0 
to 3.5 inclusive are materials that have a glass transition temperature 
greater than room temperature, and change their integrity in this 
environment and concurrently release the delivery devices. The presently 
preferred materials are pH-sensitive, nontoxic, physiologically inactive, 
and do not adversely effect the drug and a host. The materials dissolve, 
disintegrate, degrade, hydrolyze, solubilize, are digested, or undergo 
like change in this biological pH environment. The product produced, as 
the material changes and releases the tiny osmotic delivery device, is 
nontoxic, chemically inert, and physiologically inactive. One group of 
presently preferred materials are polymers, such as proteins having a 
peptide bond like gelatin of the soft or hard type. 
The materials used for forming wall 11 of delivery system 17 that maintains 
its physical and chemical integrity in an environment having a pH of 1.0 
to 3.5 inclusive, and instantly releases delivery device 13 in an 
environment having a pH of greater than 3.5 to 8.0 are materials such as 
(a) polymers having at least one acidic group that enables it to keep its 
integrity in the lower pH environment, but releases the reservoirs in the 
higher pH environment, (b) polymers that undergo changes in the higher pH 
environment by enzymes present in that environment, (c) polymer 
compositions comprising a polymer and another agent that promote 
compositions comprising a polymer and another agent that promote at the 
higher pH the disintegration of the wall, and the like. Exemplary material 
that can be used that keep their integrity at a pH of 1.0 to 3.5 inclusive 
are cellulose carboxylic acid esters phthalates, carboxylic acid ethers 
phthalates, such as cellulose ethyl phthalate, cellulose acetate 
phthalate, starch acetate phthalate, amylose acetate phthalate, 
hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose 
hexahydrophthalate, and the like. Polyacidic acids that keep their 
integrity at a pH of 1.0 to 3.5 inclusive, having acid groups in an 
associated form in the pH range, such as vinyl derivatives of partially 
hydrolyzed styrene-maleic anhydride copolymer, 
methylmeth-acrylate-methacrylic acid copolymer, polymethacrylic acid 
ester, methylacrylate-methacrylic acid ester, partial alkylene glycol 
ether esters of C.sub.1 to C.sub.4 alkyl acrylate unsaturated carboxylic 
acid anhydride co-polymers including maleic, citraconic or itaconic 
carboxylic acid anhydride, and the like. 
Representative of other polymers, and other polymer compositions that 
comprise at least two ingredients operable for the present purpose of 
keeping their integrity in a pH range of 1.0 to 3.5 inclusive, are 
polymers such as shellac, ammoniated shellac, formalized gelatin, 
polyvinyl acetate phthalate, polyvinyl acetate hydrogenphthalate, and the 
like; polymer compositions such as a mixture of hydroxyphenyl 
methylcellulose phthalate and triacetate glycerol in a weight-to-weight 
ratio of 99-to-1, shellac-formalized gelatin composition, styrene-maleic 
acid and polyvinyl acetate phthalate composition, shellac and stearic acid 
composition, and the like. 
Semipermeable materials operable for forming wall 20 of delivery device 13 
are materials insoluble in body fluids, and they are nonerodible. Typical 
materials for forming wall 20 include semipermeable polymers such as 
cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose 
acetate, cellulose diacetate, cellulose triacetate, and the like. Other 
semipermeable polymers include polyurethane and selectively permeable 
polymers including polyurethane, selectively permeable polymers formed by 
the coprecipitation of a polycation and a polyanion. Generally, 
semipermeable polymers useful for forming wall 20 will have a fluid 
permeability of 10.sup.-5 to 10.sup.-1 (cc mil/cm.sup.2 hr atm) expressed 
as per atmosphere of hydrostatic or osmotic pressure difference across 
wall 20 at the temperature of use. Procedures leading to the manufacture 
of osmotic devices are described in U.S. Pat. Nos. 3,845,770 and 
3,916,899. Procedures leading to the manufacture of an osmotic device 
embracing a drug and an expansion compartment separated by a partition are 
disclosed in U.S. Pat. No. 4,111,202. 
Dosage form 13 in another embodiment carries a pH sensitive layer 28 on the 
exterior surface of wall 20. The pH sensitive material keep its integrity, 
that is it does not dissolve or erode, in a pH of 1.0 to 3.5, and it 
looses its integrity in a pH of 3.5 to 8.0. Representative materials for 
forming layer 28 are the pH sensitive materials set forth above. In a 
presently preferred embodiment the pH sensitive materials are cellulosic 
phthalates such as a member selected from the group consisting of a 
cellulosic phthalate, cellulose acyl phthalate, cellulose alkyl phthalate, 
cellulose ethyl phthalate, cellulose acetate phthalate, starch acetate 
phthalate, amylose acetate phthalate, hydroxypropylcellulose phthalate, 
hydroxypropylmethylcellulose phthalate, alkali salts of cellulose acetate 
phthalate such as the sodium salt of cellulose acetate phthalate, alkaline 
earth salts of cellulose esters such as the calcium salt of cellulose 
acetate phthalate, ammonium salts of acidic cellulose esters such as 
ammonium salt of hydroxypropyl methylcellulose phthalate, cellulose 
acetate hexahydrophthalate, hydroxypropyl methylcellulose 
hexahydrophthalate, and the like. 
The osmotically effective solutes useful in compartment 21 include 
inorganic and organic compounds that exhibit an osmotic pressure gradient 
across semipermeable wall 20 against an external fluid. Osmotically 
effective solutes useful for the present purpose include magnesium 
sulfate, lactose, urea, inositol, raffinose, sucrose, glucose, lactose, 
sorbitol and mixtures thereof. Osmotically effective agents and their 
osmotic pressure in atmospheres are disclosed in U.S. Pat. No. 4,210,139. 
The osmotically effective osmopolymers useful for urging the drug from the 
compartment includes polymeric members that are hydrophilic, interact with 
fluids and swell to an equilibrium state, and retain a significant portion 
of the imbibed or absorbed fluid within the hydrophilic structure. The 
hydrophilic polymers from their nonhydrated state swell or expand to a 
very high degree, usually exhibiting a greater than 2 fold volume 
increase, usually a 2 to 50 fold volume increase in fluid. Representative 
hydrophilic polymers include poly (hydroxyalkyl methacrylate); poly(vinyl 
pyrrolidone) having a molecular weight of 10,000 to 360,000; poly(ethylene 
oxide) having a molecular weight from 10,000 to 5,000,000; carboxyvinyl 
polymer; sodium acidic carboxyvinyl hydrogel; potassium acidic 
carboxyvinyl hydrogel; and the like. 
In the specification and the accompanying claims, the term drug includes 
any substance that produces a local or systemic effect, or effects in 
animals, avians, reptiles and pisces. The term animal includes 
warm-blooded mammals, primates, humans, household, sport, farm, laboratory 
and zoo animals. The phrase drug formulation as used herein means drug 22 
is in compartment 21 by itself, or drug 22 is in compartment 21 mixed with 
an osmotic solute, binder or the like. The active drug that can be 
delivered includes inorganic and organic drugs that act on peripheral 
nerves, adrenergic receptors, cholinergic receptors, nervous system, 
skeletal muscles, cardiovascular system, smooth muscles, blood circulatory 
system, synoptic sites, neuroeffector junctional sites, endocrine and 
hormone systems, immunological system, reproductive system, skeletal 
system, autacoid system, tissues, organs, alimentary and excretory 
systems, inhibitory systems, histamine systems, body passageways, and the 
like. The drug includes for example, hypnotics, sedatives, psychic 
energizers, tranquilizers, anti-convulsants, muscle relaxants, 
antiparkinson, antipyretics, anti-inflammatory, analgesics, steroids, 
anticholinergics, antispasmodics, polypeptides, anesthetics, hormones, 
anti-microbials, sympathomimetics, cholinergies, diuretics, neoplastics, 
hypoglycemics, amino acids, opthalmics, vitamins, and the like. The 
delivery system in one embodiment can house osmotic delivery device 
containing the same drug, and in another embodiment the delivery system 
can house osmotic delivery devices containing like and unlike drugs. The 
inventive advantage provided by the osmotic devices each containing 
different drugs is that interaction among drugs that adversely effect each 
other is avoided, leading to better stability of delivered drug, and drug 
is delivered in the gastrointestinal tract substantially free of 
irritating the gastrointestinal mucus tissues. Also, drugs that have 
different rates of hydrolysis, different rates of oxidation, different 
rates of decomposition, different rates of delivery and different rates of 
bio-need can now be made into dosage form and dispensed essentially free 
of one drug influence or effecting another drug. The delivery system can 
house in the internal space both delivery devices and drug, which latter 
drug is available for instant use by a host, or the semi-permeable wall of 
the osmotic device can carry an enteric coating for delayed release of 
drug. The present invention provides a delivery system for administering 
drug, by making available a delivery system comprising osmotic devices 
representing a plurality of preformed passageways for dispensing and 
dispersing drug, and for enhancing its availability for use in better 
therapy. In a presently preferred embodiment the drugs include alpha 
adrenoceptor agonists with mixed alpha.sub.1 /alpha.sub.2 selectively 
including clonidine, guanfacine, guanabenz, tiamenidine, lofexidine, 
alphamethylnorepinephrine, azepexole, naphazoline, tramazoline, 
tetryzoline, osymetazoline, and xylometazoline, alpha.sub.2 agonist 
lidamidine, calcium channel blockers including loperamide, verapamil, 
diltiazers, nifedipine and congeners, fostedil, anticholinergics including 
atropine, homatropine, scopolamine, butylscopolamine, methylatropine, 
spasmolytics including papaverine and congeners, naloxone, PGE.sub.2, and 
the like. The beneficial drugs, are known to the dispensing art and in 
Pharmaceutical Sciences, by Remington, 14th Ed., 1970, published by Mack 
Publishing Co., Easton, Pa.; and The Pharmacological Basis of 
Therapeutics, by Goodman and Gilman, 4th Ed., 1970 published by MacMillan 
Co., London. 
Drug 22 can be present in compartment 21 in various forms, such as 
uncharged molecules, molecular complexes, as therapeutically acceptable 
addition salts, such as hydrochlorides, hydrobromides, sulfates, oleates 
and the like. For acid drugs, salts of metals, amines, organic cations, 
quaternary ammonium salts can be used. Derivatives of drugs such as 
esters, ethers and amides can be used. A drug that is water insoluble can 
be used in a form that is water soluble derivative thereof to serve as a 
solute, and on its release from the delivery system is converted by 
enzymes, hydrolyzed by body pH, or other metabolic processes to the 
original biologically active form. The amount of drug in compartment 21 of 
a tiny dosage delivery device 13 generally is about 10 ng to 50 ng. The 
number of devices in a delivery system is at least two or more, more 
preferably about 5 to 750, and still more preferably about 5 to 100. The 
dosage forms can be the same size or of different size combinations, 
usually from 0.5 mm to 10 mm, with a preferred size of 3 to 10 mm 
diameter. 
The drug delivery device 13 used for the purpose of the invention, is 
manufactured by standard techniques. For example, in one embodiment drug 
and a binder are mixed into a solid, semi-solid, or pressed into a 
miniature shape formed by conventional methods. Then, wall forming 
material is applied by molding, spraying or dipping the pressed drug shape 
into the wall forming material. In another embodiment, a wall can be cast, 
shaped to the desired dimensions that surround compartment 21, the 
compartment filled with drug, closed, and a passageway drilled through the 
wall. For osmotic devices manufactured smaller than 2 mm in diameter, the 
passageway is preferably made by the in situ method described in U.S. Pat. 
No. 4,016,880. In a presently preferred embodiment the delivery device is 
made by using an air suspension technique. This process consists in 
compressing a drug, and then suspending and tumbling the drug in a wall 
forming composition until the wall is applied around the drug. Next, after 
drying, a passageway is drilled in the wall. 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 forming techniques such as pan coating can be used in which materials 
are deposited by successive spraying of the polymer solution on the drug, 
or solute, accompanied by tumbling in a rotating pan. Generally, a 
semipermeable wall will be about 0.01 to 10 mils thick, usually 1 to 3 
mils. Of course, thinner and thicker walls are within the scope of the 
invention. 
Delivery system 17 comprising body member 10 can be made by procedures such 
as dipping a mold element, having a shape corresponding to the shape 
illustrated in FIGS. 1a or 1b, for example, into a bath of a wall 11 
forming material, such as a solution of aqueous gelatin. The mold element 
is submerged within the aqueous gelatin to form the desired coat on the 
mold element. Next, the coated mold is pulled from the solution, allowed 
to cool, and then stripped from the mold to yield the wall member with an 
internal lumen. The wall can be made from enteric material by dissolving, 
for example, dydroxypropyl methylcellulose phthalate in an aqueous 
solution of an alkali base to obtain an aqueous solution corresponding to 
the alkali metal salt of hydroxypropyl methylcellulose phthalate. Typical 
alkali bases are sodium carbonate, potassium carbonate, sodium hydroxide, 
and the like. Next, an aqueous gelatin solution is added to the solution 
of the alkali metal salt of hydroxypropyl methylcellulose phthalate, and 
molds immersed into the solution, withdrawn and the materials on the molds 
cooled at room temperature, or lower. Next, the capsule portion is removed 
from the mold. Manufacturing procedures for making capsules are disclosed 
in U.S. Pat. Nos. 1,527,659; 2,299,039; and 3,826,666. 
Exemplary solvents suitable for manufacturing semi-permeable wall 20 are 
inert inorganic and organic solvents that do not adversely harm the wall 
forming materials, the drug and the final osmotic device. The solvents 
broadly include aqueous solvents, alcohols, ketones, esters, ethers, 
aliphatic hydrocarbons, halogenated solvents, cycloaliphatic aromatics, 
heterocyclic solvents and the like. Typical solvents include acetone, 
methanol, ethanol, isopropyl alcohol, methyl acetate, ethyl acetate, 
methyl isobutyl ketone, n-hexane, methylene chloride, ethylene dichloride, 
mixtures such as acetone and water acetone and methanol, acetone and ethyl 
alcohol, methylene dichloride and methanol, ethylene dichloride and 
methanol, and mixtures thereof. 
DESCRIPTION OF EXAMPLES 
The following examples will serve to further illustrate 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, drawings, and the accompanying claims. 
EXAMPLE 1 
First, 100 mg of procainamide hydrochloride and 5 mg of binder polyvinyl 
pyrrolidone are blended into a homogeneous composition and passed through 
a 20 mesh screen to form a number of pre-cores of drug. The pre-cores next 
are compressed into round cores about 5 mm in diameter and then 
transferred to an air suspension machine. The compressed drug cores 
contain about 20 mg of drug and are coated with cellulose acetate having 
an acetyl content of 32% using a 5% polymer solution in dioxane to produce 
tiny osmotic drug delivery devices having a semi-permeable wall about 6 
mils thick. After the delivery devices are dried for 10 days at about 
55.degree. C., an osmotic passageway about 4 mils in diameter is laser 
drilled through the semipermeable wall. Finally, a number of receiving 
capsules are filled with 5 osmotic devices and capped with the closing 
portion of the capsule to yield the delivery system. The wall of the 
delivery system comprises polymeric gelatin that releases the delivery 
devices in an environment having a pH of 1.0 to 3.5 inclusive. 
EXAMPLE 2 
A delivery device is made by first preparing drug reservoirs comprising 
potassium chloride by blending 1 kg of potassium chloride and 3 ml of a 
20% solution of acacia to form a homogeneous blend. Next, the blend is 
passed through an extrusion granulation machine, dried at 
115.degree.-120.degree. F. for 12 hours, and the reservoir forming cores 
passed through a 20 mesh screen. The cores are coated next in an air 
suspension machine with a 5% solution of cellulose acetate in a methylene 
chloride-methanol solvent, 89:11 wt:wt, with a semipermeable wall 7 mils 
thick. The coated drug is dried at 55.degree. C. for 48 hours in an air 
oven, and then osmotic passageways are laser drilled in each device. The 
passageway had a diameter of about 42.times.10.sup.-1 mils. 
The tiny osmotic delivery devices are transferred to a feeding hopper and 
15 devices are fed into the receiving portion of a capsule, and then the 
filled portion is moved to the next position in the filling line where the 
receiving portion is telescopically capped with an engaging cap portion to 
produce the completed delivery system. The receiving and cap portions are 
made from a wall forming composition comprising cellulose acetate 
phthalate and formalized gelatin, which composition keeps its integrity at 
a pH of 1.0 to 3.5 inclusive, and releases the tiny osmotic devices at a 
pH of greater than 3.5 to 8.0. 
EXAMPLE 3 
Drug delivery devices are prepared according to the procedures of the above 
examples. The drug reservoirs for this example are made from 375 g of 
aminophylline, 15.5 g of mannitol, and 1.5 g of magnesium stearate, and 
formulated into tiny compressed drug cores. The cores are coated with a 
semipermeable wall of cellulose acetate having an acetyl content of 38.3%, 
and a passageway laser drilled therethrough. Then, 15 of the tiny drug 
delivery devices are surrounded by a wall having first or inner lamina of 
gelatin, and then a second, or outer lamina of hydroxypropyl 
methylcellulose phthalate is laminated onto the inner lamina by dipping 
the delivery system with a bath containing hydroxypropyl methylcellulose 
phthalate. 
EXAMPLE 4 
The drug delivery systems prepared according to Example 1 are placed in an 
air suspension machine, and a volatile coating composition comprising an 
acrylic based resin in isopropyl alcohol is injected through a port into 
the machine for applying a coat onto the delivery system. 
EXAMPLE 5 
An osmotic delivery device for the controlled and continuous delivery of 
the beneficial drug hydralazine hydrochloride to a biological environment 
of use is made as follows: first a compartment forming composition is 
compounded from 50 mg of hydralazine hydrochloride, 208.5 mg of mannitol, 
8 mg of hydroxypropyl methylcellulose 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 70/30 w/w % ethanol-water solution and the hydralazine 
mannitol mixture 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 a forced air 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. Then, 35 mm of the hydralazine drug 
formulation reservoir is pressed under a pressure head into a 4 mm core 
and then coated in an air suspension machine with a wall of semipermeable 
cellulose acetate composition comprising 40% cellulose acetate having an 
acetyl content of 32%, 42% cellulose acetate having an acetyl content of 
39.8%, and 18% hydroxypropyl methylcellulose, coated from an 80 to 20 
parts by weight solvent of methylene chloridemethanol solvent. The coated 
osmotic device is dried in a forced air oven at 50.degree. C. for one 
week, and then a laser passageway is drilled through the semipermeable 
wall. 
A different reservoir forming composition comprising 19 mg of metoprolol 
fumarate, 1.4 mg of sodium bicarbonate, 1.6 mg of polyvinyl pyrrolidone 
and 0.32 mg of magnesium stearate is made by first mixing the metoprolol 
fumarate with sodium bicarbonate and passing the mixture through a 40-mesh 
screen, then, the polyvinyl pyrrolidone is mixed with 2 ml of an ethanol 
and 1 ml of water solution, and the freshly prepared polyvinyl pyrrolidone 
solution is added slowly with mixing to the metoprolol fumarate sodium 
bicarbonate mixture. The ingredients are mixed for 20 minutes, passed 
through a 10-mesh screen and dried in a forced air oven for 24 hours. 
Next, the dried blend is passed through a 20-mesh screen, placed in a 
mixer, the magnesium stearate added and the ingredients again blended to 
yield the reservoir composition. Then, the metoprolol fumarate drug 
formulation is compressed into a solid core and coated in an air 
suspension machine with a wall of semipermeable cellulose acetate 
composition comprising 40% cellulose acetate having an acetyl content of 
32%, 42% cellulose acetate having an acetyl content of 39.8%, and 18% 
hydroxypropyl methylcellulose, from an 80 to 20 parts by weight solvent of 
methylene chloride-methanol solvent. The coated osmotic device is dried in 
a forced air oven at 50.degree. C. for one week, and then a laser 
passageway is drilled through the semipermeable wall. Finally a plurality 
of the osmotic devices containing the hydralazine and a plurality of the 
osmotic devices containing the metoprolol are charged into the lumen of a 
housing to yield the delivery system. The osmotic devices on their release 
from the housing in a gastrointestinal tract deliver the drugs with 
dispersion throughout the tract substantially free of tissue irritation. 
It will be appreciated by those versed in the drug dispensing art that the 
present invention advances the state-of-the-art by providing (a) a 
delivery system that can provide in vivo a multiplicity of tiny osmotic 
drug delivery devices that can deliver drug-in-solution as the devices 
travel through the biological environment; (b) a delivery system that can 
provide tiny osmotic devices for minimizing gastrointestinal irritation; 
(c) a delivery system that can provide tiny osmotic devices for continuous 
and steady release for producing constant and steady absorption of 
delivered drug; and (d) provide a delivery system that can deliver drug 
from a plurality of tiny osmotic device in solution in the stomach and/or 
the intestine over time. Also it will be understood by those knowledgeable 
in the delivery art that many embodiments of this invention can be made 
without departing from the spirit and scope of the invention, and the 
invention is not to be construed as limiting, as it embraces all 
equivalents thereof.