Dosage form for delivering acid sensitive beneficial agent

A dosage form is disclosed, which dosage form comprises an outside wall and an inside wall, which inside wall comprises means for changing its structural integrity in response to fluid having a pH greater than 5 that enters the dosage form, thereby changing the pH environment inside the dosage form and concomitantly causing the inside wall to change its structural integrity, thus causing the outside wall to collapse and be easily eliminated from a host.

FIELD OF THE INVENTION 
This invention pertains to both a novel and unique dosage form. The dosage 
form comprises an inner wall, an outer wall and a compartment comprising a 
beneficial agent that exhibits in solution a pH less than 7. In operation 
the beneficial agent is continuously delivered from the dosage form and at 
the end of the delivery period alkaline solution present in the 
environment of use enters the dosage form changes and alters the 
structural integrity of the inner wall, whereupon the dosage form 
collapses thereby facilitating discharge of the dosage form from the 
environment of use. 
BACKGROUND OF THE INVENTION 
Since the beginning of antiquity, both pharmacy and medicine have sought a 
dosage form for the controlled administration of a beneficial drug. The 
first written reference to a dosage form is in the Eber Papyrus written 
about 1552 B.C. The Eber Papyrus mentioned 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 until the Arab physician Rhazes, 863-925 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, 936-1009 A.D. The manuscripts described a tablet 
formed from the hollow impressions in two matched-facing tablet molds. 
Pharmacy and medicine waited about 800 years for the next innovation in 
dosage forms when in 1833 Mothes invented the soft gelatin capsule for 
administering a drug. Fifteen years later, in 1848 Murdock invented the 
two-piece hard gelatin capsule. The coating of pills with tolu was first 
recommended about 1860, and in 1884 Unna introduced enteric coating with 
Keratin coated pills. 
The technical valve of sustained released dosage forms was recognized by 
Lipowski who, in 1938, discussed the desirability of a slow and constant 
supply of a drug to an organism. Lipowski's patents were the first to 
describe an oral dosage for consisting of a number of small drug 
containing beads, having different thickness of coating, utilized to give 
a slow and constant release of drug on ingestion. In 1952 Blythe conceived 
of the use of multiple small pellets which could be coated and which, 
independent of pH, would have reproducible release rates and prolonged 
drug release. Blythe uses varying coating thicknesses of time-delay 
materials in a single capsule. 
The next quantum and profound advancement in dosage forms came in 1972 with 
the invention of the osmotic delivery system by inventors Theeuwes and 
Higuchi. This unique osmotic dosage form is manufactured in one embodiment 
for oral use, and in this embodiment it embraces the appearance of a 
tablet with at least one delivery portal. The delivery portal can be 
preformed or formed by leaching a pore former during operation of the 
dosage form. It is the first oral dosage form that delivers throughout the 
entire gastrointestinal tract a known amount of drug per unit time at a 
controlled rate of delivery. The oral osmotic device maintains its 
physical and chemical integrity during the prolonged period of time it 
transits the total length of the gastrointestinal tract. 
The above discussed osmotic dosage form represents an outstanding and 
pioneering advancement in the art and science of drug delivery. Now it has 
been discovered a need exists for a delivery system that loses its 
physical and chemical integrity at the end of the delivery period for 
discharging the dosage form from the environment of use, mainly the 
gastrointestinal tract. The need exists for a dosage form that loses its 
structural integrity, that is for a dosage form that becomes compressible 
and/or self-destructs for avoiding possible retention of the empty dosage 
form within the gastrointestinal tract. 
OBJECTS OF THE INVENTION 
Accordingly, in view of the above presentations, it is an immediate object 
of this invention to provide a novel and useful dosage form that satisfies 
that critical need associated with the prior art. 
Another object of the invention is to provide a novel dosage form that 
delivers substantially all of its beneficial agent from the dosage from 
followed by the dosage form collapsing for easy passage from the 
gastrointestinal tract. 
Another object of the present invention is to provide a dosage form 
manufactured as an osmotic device shaped, sized, structured and adapted 
for the controlled and continuous delivery of a beneficial drug throughout 
the gastrointestinal tract followed by the device losing its structural 
integrity at the end of the delivery period for facilitating easy exit 
from the tract. 
Another object of the present invention is to provide a controlled time 
release dosage form comprising an inner wall that breaks down at the end 
of the delivery period for enhancing the peristaltic expulsion of the 
dosage form from the environment of use. 
Another object of the present invention is to provide a dosage that 
delivers a drug constantly for sustained blood levels in the body as a 
result of controlled and sustained release of drug in the gastrointestinal 
tract, comprising the stomach and the intestines, and which dosage form 
under the influence of the alkaline environment of the intestine alters 
and changes its structure for enhancing its peristaltic expulsion from the 
intestine. 
Another object of the present invention is to provide an oral, osmotic 
dosage form for delivering essentially all of its drug at a controlled 
rate in the stomach and in the intestines, with the dosage form keeping 
its physical and chemical integrity during the drug dispensing in the 
stomach and intestine and then losing its physical and chemical integrity 
after the dispensing period in the intestine, and which dosage form is 
relatively economical in cost to manufacture, provides the physician with 
a dependable dosage form, and is well-adapted for practical and acceptable 
patient use. 
Another object of the present invention is to provide an oral, osmotic 
device that dispenses drug at a rate controlled by the device in the 
stomach and in the intestine and then in response to the biological 
environment of the intestine adapts a structure that is readily discharged 
from the animal body. 
Other objects features and advantages of this invention will be more 
apparent to those versed in the dispensing art from the following detailed 
specification, taken in conjunction with the drawings and the accompanying 
claims.

In the drawing figures, and in 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 drawing figures, as well as 
embodiments thereof, are further described elsewhere in the disclosure. 
DETAILED DESCRIPTION OF THE DRAWING FIGURES 
Turning now to the drawing figures in detail, which drawing figures are an 
example of the dosage form provided by this invention, and which examples 
are not to be construed as limiting the invention, one example of the 
dosage form is illustrated in FIG. 1 and designated by the numeral 20. In 
FIG. 1, dosage form 20 comprises a body member 21 comprising a wall 22 
that surrounds and forms an internal compartment not seen in FIG. 1. 
Dosage form 20 further comprises at least one exit means 23 for connecting 
the interior of dosage form 20 with the exterior environment of use. 
FIG. 2 illustrates dosage form 20 of FIG. 1 comprising body 21, wall 22, 
and exit means 23. Wall 22 comprises an outer wall 24 and an inner wall 
25. Wall 22 comprising outside wall 24 and inside wall 25 surrounds and 
defines an interior compartment 26. Composite wall 22, comprising outside 
wall 24 and inside wall 25 at least in part, or totally, comprises a 
composition that is permeable to the passage of an exterior fluid present 
in the environment of use. Outside wall 24 comprises a polymeric 
composition that is inert and maintains its physical and chemical 
integrity during the dispensing life time of dosage form 20. The phrase 
"physical and chemical integrity" denotes outside wall 24 does not lose 
its structure and it does not change during the dispensing life of dosage 
form 20. Typical materials for forming outside wall 24 comprises 
selectively semipermeable polymers known as osmosis and as reverse osmosis 
polymers. These polymeric compositions comprise a cellulose ester, 
cellulose ether, cellulose ester-ether, cellulose acylate, cellulose 
diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, 
and cellulose triacetate. Other semipermeable polymeric compositions 
include cellulose acetate ethyl carbamate, cellulose acetate methyl 
carbamate, cellulose acetate ethyl carbamate, cellulose acetate succinate, 
cellulose acetate dimethyl-aminoacetate, cellulose acetate ethylcarbamate, 
cellulose acetate chloracetate, cellulose dipalmate, cellulose 
dioctanoate, cellulose acetate valerate, cellulose acetate succinate, 
cellulose propionate succinate, and the like. In a presently preferred 
embodiment outside wall 24 comprises a thickness of from 0.01 mm to 3 mm. 
Semipermeable polymers are known to the dispensing art in U.S. Pat. Nos. 
3,845,770; 3,916,899; 4,160,020 and 4,250,108. 
Inside wall 25 comprises a polymeric formulation that is sensitive to 
changes in pH. Wall 25 keeps its physical and chemical integrity in the 
presence of beneficial acidic agents that form an acidic solution having a 
pH less than 4 with fluid that enters dosage form 20. Inside wall 25 
maintains its integrity throughout the dispensing of the beneficial agent 
from dosage form 20. Inside wall 25, in a preferred embodiment, loses its 
integrity when a solution having a pH greater than 5 present in the 
environment of use enters the dosage form and causes inside wall 25 to 
lose its integrity. The loss of integrity of inside wall 25 is accompanied 
by a collapse of outside wall 24 thereby increasing its discharge from the 
environment of use. Representative materials for forming inside wall 25 
are materials that dissolve or disintegrate on exposure to the alkaline 
solution or the alkaline environment inside dosage form 20. The solution 
also includes the intestinal buffer solution of the gastrointestinal 
tract. The materials for forming inside wall 25 include ionizable 
polyacids, frequently a long-chain polymer with ionizable carboxyl groups 
and the like. Materials for forming inside wall 25 include keratin, 
keratin over sandarac-tolu, B-naphthyl benzoate and acetotanin, balsam of 
Peru, balsam of tolu, shellac, gum resin and salol-shellac formalized 
gelatin, myristic acid-hydrogenated castor oil, shellac n-butyl stearate, 
cellulose carboxylic acid phthalate, cellulose ethyl phthalate, cellulose 
acetate phthalate, starch acetate phthalate, amylose acetate phthalate, 
hydroxypropyl methylcellulose phthalate, hydroxypropyl ethylcellulose 
phthalate, cellulose acetate hexahydrophthalate, hydroxypropyl 
methylcellulose hexahydrophthatate, polyacylic acid, polyacylic acid 
co-esters, and the like. Inside wall 25 is preferably from 1 mm to 5 mm 
thick. In in vitro test for determining the disintegration rate and time 
of a material in an alkaline environment is reported in Pharmaceutical 
Technology, by Chambliss, Sept. 1983. Materials sensitive to pH are 
reported in Remington's Pharmaceutical Sciences. 14th Ed., pp 604 to 605, 
1965; and in Biopharmaceutics and Relevant Pharmacokinetics, 1st Ed., pp 
158 to 165, 1971. 
Internal compartment 26 comprises a beneficial agent 27, that is in a 
presently preferred embodiment a beneficial drug. The drug that can be 
housed in compartment 26 includes any physiologically or pharmacologically 
active drug that produces a local or a systemic effect in animals. The 
term animals includes warm-blooded mammals, humans, primates, household, 
sport, farm and zoo animals. The active drugs that can be delivered 
include inorganic and organic drugs without limitations, drugs that can 
act on the central nervous system, depressants, hypnotics, sedatives, 
psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, 
antiparkinson, anti-inflammatories, local anesthetics, muscle 
contractants, antimicrobials, antimalarials, hormonal agents, 
contraceptives, diuretics, sympathomimetics, antiparasitics, neoplastics, 
hypoglycemics, ophthalmics, diagnostics, cardiovascular drugs and the 
like. The beneficial drugs useful for the purpose of the present invention 
comprises drugs, or a drug and an acidic osmagent, or a drug and an acidic 
buffer, that exhibit an acidic pH in solution. The beneficial drugs are in 
a presently preferred embodiment the acid addition drugs. Examples of 
non-toxic, pharmaceutically acceptable acid addition salts are 
hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, propionic, 
citric, oxalic, maleic, and the like. More specific examples of acid drugs 
that exhibit a pH of less than 4 comprise a member selected from the group 
consisting of cyclizine hydrochloride, thiethylperazine maleate, 
diphenoxyleate hydrobromide, phentolamine mesylate, cyclopentolate 
hydrochloride, mepenzolate bromide, cyclomethycaine sulfate, 
tripelennamine citrate, trimeprazine tartrate, and the like. The 
beneficial drugs are known to the art in Pharmaceutical Sciences, by 
Remington, 14th Ed., 1979 published by Mack Publishing Co., Easton, Pa.; 
The Drug, The Nurse, The Patient, Including current Drug Handbook, 
1974-76, by Falconer et al., published by Saunders Co., Philadelphia, Pa.; 
and Physician's Desk Reference, 4Oth Ed., 1986, published by Medical 
Economics Co., Oradell, N.J. 
The term "pH" as used herein denotes the pH valve of an aqueous solution as 
a number describing its acidity or alkalinity. The pH valves are 
determined by acid-base titrations, and by using electronic pH meters as 
reported in the Encyclopedia Of Chemistry, 2nd Ed., pages 799 to 800, 
1966, published by Van Nostrand-Reinhold Co., New York, N.Y. The effects 
of an acidic solution, or a alkaline solution on the integrity of a pH 
sensitive materials in direct contact with the solution is ascertainable 
by the procedures described in J. Amer. Pharm. Assoc. Vol. 27, pp 379 to 
384, 1938; and The Pharmacopeia Of The United States Of America, 18th Ed., 
pp 932 to 934, 1970. 
FIG. 3 is a opened view of another dispensing dosage form 20 provided by 
this invention. In FIG. 3, dosage form 20 comprises body 21, and dual wall 
22. Dual wall 22 comprises outside wall 24 that permits the passage of 
fluid into dosage form 20 and inside wall 25 formed of an 
alkaline-sensitive material. Inside wall 25 loses its integrity after the 
dispensing of drug from dosage form 20 and in the presence of biological 
alkaline fluid from the intestine and the colon that enters dosage form 20 
after the dispensing of the drug. Dual wall 22 surrounds interior 
compartment 26 comprising at least one exit means 23. 
Internal compartment 26 of FIG. 3, in a presently preferred embodiment, 
houses a first layer 27 comprising a beneficial drug identified by dots, 
and an expandable layer 28, identified by dashes. Drug formulation 27 was 
described above in the presentation pertaining to FIG. 2. Expandable layer 
28 comprises a hydrophilic, hydrogel formulation that exhibits fluid 
absorbing and/or imbibing properties. The hydrophilic materials forming 
layer 28 comprises a hydrophilic polymeric formulation that can interact 
with water and aqueous biological fluids and swell or expand to an 
equilibrium state. In operation, first layer 27 and second layer 28 
cooperate to deliver drug formulation from dosage 20, with second layer 
absorbant fluid expanding and exerting pressure against first layer 27. 
First layer 27 optionally absorbs fluid and forms a dispensable 
formulation and by the combined operations second layer 28 expands against 
first layer 27 and urge it from compartment 26. In this manner, drug 
formulation is delivered through exit means 23 to the environment of use. 
The hydrophilic hydrogel composition comprising layer 28 swells or expands 
to a very high degree, usually exhibiting from a nonhydrated state, a 2 to 
50 fold increase in volume. Representative hydrophillic hydrogels consists 
of a member selected from the group consisting of poly(hydroxyalkyl 
methacrylate) having a molecular weight of 15,000 to 5,000,000; 
poly(vinylpyrrolidone) having a molecular weight of about 10,000 to 
360,000; poly(vinyl alcohol) having a low acetate content and lightly 
cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a 
degree of polymerization of from 200 to 30,000; poly(ethylene oxide) 
having a molecular weight from 10,000 to 6,000,000; the sodium salt of 
carboxymethylcellulose having a molecular weight from 10,000 to 2,000,000; 
acidic carboxy polymer known as carboxypolymethylene and carboxyvinyl 
polymers consisting of acrylic acid lightly cross-linked with polyallyl 
sucrose and sold under the trademark Carbopol.RTM., acidic carboxypolymer 
having a molecular weight of 200,000 to 6,000,000, including sodium acidic 
carboxyvinyl hydrogel and potassium acidic carboxyvinyl hydrogel; 
Cyanamer.RTM. polyacrylamide; and the like. The representative polymers 
are known in the Handbook Of Common Polymers, by Scott and Roff, published 
by the Chemical Company, Cleveland, Ohio; ACS Symposium Series, No. 31, by 
Ratner and Hoffman, pp 1 to 36, 1976, published by the American Chemical 
Society; and in Recent Advances In Drug Delivery Systems by Schacht, pp 
259 to 278, published by Plenum Press, N.Y. 
FIG. 4 depicts in opened section another delivery dosage form 20 provided 
by the invention. Dosage form 20 in FIG. 4 comprise.s body member 21, wall 
22 comprising outside wall 24 and inside 25, compartment 26 comprising 
drug formulation 27 and exit means 23. The expression exit means as used 
herein comprises means and methods suitable for releasing drug formulation 
27 from compartment 26. The expression "at least one passageway" includes 
aperture, orifice, bore, pore, porous element through which drug can 
migrate, a hollow fiber, capillary tube and the like. The expression 
includes also a material that erodes, or is leached from wall 22 in the 
fluid environment of use to produce at least one passageway in the dosage 
form. Representative materials suitable for forming at least one 
passageway, or a multiplicity of passageways include an erodible 
poly(lactic) or poly(glycolic) acid member in the wall, a gelatinous 
filament, leachable materials such a fluid removable pore forming 
polysaccharides, salts, oxides or salt alcohols, and the like. A 
passageway or plurality of passageways can be formed through the outside 
and inside walls by leaching a material such as sorbitol from the walls to 
produce a controlled release passageway. Dosage form 20 can be constructed 
with one or more passageways in spaced apart relation on more than one 
surface of a dosage form. The passageway can be a microporous member 
inserted into the wall, with the microporous member preformed or formed 
during operation of the dosage form. Passageways and equipment for forming 
passageways are disclosed in U.S. Pat. Nos. 3,916,899; 4,063,064 and 
4,088,864. Passageways of controlled dimensions in an osmotic system 
formed by leaching a pore former such as sorbitol are disclosed in U.S. 
Pat. No. 4,200,098. 
The amount of drug present in the dosage form generally is an amount 
sufficient for performing a therapeutic program. Generally, the dispensing 
dosage form will contain from 0.05 ng to 1500 mg, or more with individual 
dosage forms containing, for example, 25 ng, 1 mg, 25 mg, 50 mg, 125 mg, 
250 mg, 750 mg, and the like. The dosage form can be administered once, 
twice daily, or like, over a prolonged period of one day to one year, or 
longer. The phrase drug formulation as used for the purpose of this 
invention denotes the drug is present in the compartment neat, or with 
tablet forming excipients. 
Wall 22, comprising outside wall 24 and inside wall 25, surrounding drug 
formulation 27, or surrounding drug formulation 27 and expandable member 
28, in the various embodiments can be formed using an air suspension 
procedure. The procedure consists in suspending and tumbling the 
compartment forming members and wall forming compositions in a current of 
air and using the wall forming composition until the inside wall, and then 
the outside wall is applied to the compartment forming members. The air 
suspension procedure is well-suited for independently forming each wall in 
separate operations. The air suspension procedure is described in U.S. 
Pat. No. 2,799,240; in J. Am. Pharm. Assoc., Vol. 48, pp 451 to 459, 1959; 
and ibid, Vol. 49, pp 82 to 84, 1960. The wall-forming composition can be 
applied with a Wurster.RTM. air suspension coater, or an Aeromatic.RTM. 
air suspension coater. Other wall-forming techniques such as pan coating 
can be used for providing the dosage form. In the pan coating system, the 
wall forming compositions are deposited by successive spraying of the 
composition accompanied by tumbling in a rotating pan. A pan coater is 
used to produce a thicker wall. Finally, the wall coated dosage form is 
dried in a forced air oven at 50.degree. C. for a week, or in a 
temperature and humidity controlled oven, at 50.degree. C. and 50.degree. 
C. R.H. for 24 hours. 
Exemplary solvents operable for manufacturing a wall of a dosage form 
include inert organic and inorganic solvents that do not adversely harm 
the wall forming material, and the final dosage form. The solvents broadly 
include a member selected from the group consisting of an alcohol, ketone, 
ester, ether, aliphatic, halogenated, cycloaliphatic, aromatic, 
heterocyclic, aqueous solvents, and the like. 
The compartment forming members comprising a drug and other ingredients are 
manufactured in one process by blending a powdered drug and other core 
forming ingredients in a fluid bed granulator. After the powdered 
ingredients are dry blended in the granulator, a granulating fluid, for 
example, polyvinyl pyrrolidone in water, is sprayed onto the powdered 
member. The coated powder is dried in the granulator. After drying a 
lubricant such as magnesium stearate is added to the granulator. The 
granules are then pressed and wall coated with a wall forming composition. 
The dosage form of the invention can be manufactured by other manufacturing 
techniques. For example, in one manufacture the beneficial drug and other 
compartment core forming materials are blended and pressed into a solid 
layer. The layer possesses dimensions that corresponds to the internal 
dimensions of the area occupied in the dosage form. Optionally, the drug 
formulation can be blended with a solvent, mixed by conventional methods 
such as ballmilling, callendering, stirring, or rollmilling and then 
pressed into a preselected shape. The compressed compartment forming mass 
then is coated with an inner and outer wall. The wall forming composition 
can be applied by press coating, molding, spraying, dipping or air 
suspension procedures. The air suspension and air tumbling procedures 
comprise suspending and tumbling the pressed composition until surrounded 
with the respective walls. Dosage forms comprising a drug formulation 
layer in contacting arrangement, and then coated with the inner and outer 
walls. 
In another manufacture, the dosage form is made by the wet granulation 
technique. In the wet granulation technique, the drug is blended with 
other compartment forming ingredients using an organic cosolvent, such as 
isopropyl alcohol-methylene dichloride, 80/20 v/v (volume/volume) as the 
granulation fluid. The ingredients are passed through a 40 mesh screen and 
blended in a mixer. Then, the blend is dried for 18 to 24 hours at 
42.degree. C. in a forced air oven. Next, a lubricant is added to the dry 
blend, and the newly formed mixture put into milling jars and mixed on a 
jar mill for 5 to 15 minutes. The composition is pressed into a layer in a 
Manesty.RTM. layer press at a maximum load of 2 tons. The pressed mass is 
fed to a Kilian.RTM. dry cota press and coated with an exterior wall. 
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 
anyway, as these examples and other equivalents thereof will become more 
apparent to those versed in the dispensing art in the light of the present 
disclosure, the drawing figures and the accompanying claims. 
EXAMPLE 1 
A dosage form is manufactured for delivering a beneficial drug as follows: 
first, a compartment-forming composition is prepared by dissolving 4 g of 
polyvinyl pyrrolidone in 30 ml of a cosolvent consisting of 95% ethanol 
and 5% distilled water, and then blending the moist polyvinyl pyrrolidone 
with a composition comprising 475 g of cimetidine hydrochloride and 10 g 
of cross-linked sodium carboxymethyl cellulose previously passed through a 
40 mesh stainless steel sieve to yield a homogeneous blend. Next, an 
additional 70 ml of the cosolvent consisting of ethanol and distilled 
water is added to the cimetidine hydrochloric acid blend to form a wet 
granulation. The wet granulation is passed through a 10 mesh stainless 
steel sieve and then dried at 50.degree. C. for 18 to 20 hours. Then 5 g 
of magnesium stearate is added to the dried granulation which is passed 
through a 20 mesh stainless steel sieve. The final blend is compressed 
into number of cores of drug having an average core weight of 742.2 mg and 
a hardness of 12-18 kp. 
The individual cores were coated with an inside wall-forming composition 
comprising 30% hydroxypropylmethylcellulose phthalate, 15% cellulose 
acetate having an acetyl content of 39.8%, 45% sorbitol and 10% 
polyethylene glycol. The wall-forming coating solution consists of 80/20 
(v/v) acetone/water blend. The total solid content is 3%, with mixing 
conducted with a Cole-Parmer.RTM. stirrer. The wall forming composition is 
coated around the cores in an air suspension machine. The first applied 
inside wall is about 4 mils thick. Next, an outside wall about 0.5 mil 
thick comprising cellulose acetate having an acetyl content of 32% is 
applied in contacting arrangement over the first formed inside wall. The 
second form outside semipermeable wall is applied using a cosolvent 
comprising methylene chloride/methanol, 80/20, (v/v) with a total solid 
content of 2%. The wall forming semipermeable composition is mixed with a 
Cole-Parmer.RTM. mixer and applied with an Aeromatic.RTM. air suspension 
coater. The final dosage form has a pair of spaced apart passageways of 
0.38 mm diameter. The dosage forms, after dispensing its drug in a 
distilled water environment is transferred to an artificial intestinal 
fluid environment. In the artificial intestinal fluid, the inside wall 
undergoes dissolution in the fluid, as the inside wall dissolves due to 
hydroxide ions from the artificial intestinal fluid entering the dosage 
form, thereby causing the dosage form to collapse. 
EXAMPLE 2 
The procedure described in Example 1 is repeated with all condition as 
previously set forth, except that in this example the outside 
semipermeable wall consists of cellulose acetate having an acetyl content 
of 36%, or cellulose acetate having an acetyl content of 39.8%. The 
initial collapse pressure of the cellulose acetate 36% wall, and the 
cellulose acetate 39.8% outside wall overcoated around the inside wall of 
Example 1 is 150 mm Hg, and 150 mm Hg respectively. The walls exhibited a 
collapse pressure of 60 mm Hg, are 60 mm Hg when exposed to artificial 
intestinal fluid, indicating the interior wall dissolves and weakens as to 
lose its structural integrity and continuity in the structural integrity 
and continuity in the presence of artificial intestinal fluid exhibiting a 
pH greater than 4. The dissolution of the wall in intestinal fluid 
enhances the easy of expulsion of the dosage form through the anorectal 
route from the gastrointestinal tract. 
EXAMPLE 3 
A dosage form for dispensing a beneficial drug having an acidic function is 
manufactured as follows: first, 600 g of indomethacin, 2220 g of 
polyethylene oxide having a molecular weight of 200,000 and 150 g of 
hydroxypropyl methyl cellulose are blended and screened 40 mesh screen and 
then added to a mixing bowl, and dry mixed for 15 to 20 minutes. Next, 
2000 ml of anhydrous, denatured ethanol is slowly added and mixing 
continued for 15 to 20 minutes more. Then, the wet mass is passed through 
a 16 mesh screen, spread on a white paper overnight and air dried at room 
temperature. Next, the dry mass is passed through a 16-mesh screen and 30 
g of magnesium stearate added and blended therewith for 5 minutes, to 
yield the drug containing core-forming composition. 
Next, 4480 g of polyethylene oxide having a molecular weight of about 
5,000,000 is screened through a 40 mesh screen. Then, 2030 g of sodium 
chloride, and 350 g of hydroxypropyl methylcellulose and mixed for 15 to 
20 minutes. Next, a granulating solvent consisting of 6 L of ethanol 
absolute and 100 ml of methanol is slowly added to the blending 
ingredients and the wet granulation mixed for 5 to 10 minutes. The wet 
granulation is removed from the mixer and then passed through a 16 mesh 
screen onto paper-lined oven trays. The trays are placed into an oven at 
30.degree.-35.degree. C. and allowed to dry for 24 hours. After drying the 
dry granulation is passed through a 16-mesh stainless steel screen and 30 
g of magnesium stearate added thereto. Then, all the ingredients are 
blended for 15 minutes to provide a uniform, homogeneous hydrophilic, 
hydrogel composition. 
Next, a number of drug cores weighing 60 mg are pressed into a layer and 
then placed into contacting arrangement with a 240 mg layer of the 
hydrophilic, hydrogel composition. The first and second layers are 
surrounded with a wall forming composition 22.5% 
hydroxypropylmethylcellulose phthalate, 25% hydroxypropylmethylcellulose, 
25% polyethylene glycol, 22.5% cellulose acetate having an acetyl content 
of 39.8% and 5% of adipic acid. The wall is applied from a cosolvent 
comprising methylene chloride/methanol, 80/20 (v/v) with a total solid 
content of 4%. The wall forming ingredients were mixed with a 
Cole-Parmer.RTM. stirrer and applied with an Aeromatic.RTM. air suspension 
coater. 
Then, a semipermeable wall is coated around the inside wall. The outside 
wall cellulose acetate having an acetyl content of 39.8%. The 
semipermeable wall is applied with a cosolvent comprising methylene 
chloride/methanol, 90/10, (v/v), with a solid content of 2%. The wall 
forming ingredients are mixed with a Cole-Parmer.RTM. stirrer, and coated 
with an Aeromatic.RTM. air suspension coater. The dosage form had a 0.38 
mm orifice, and after dispensing its drug layer, the inside wall in 
artificial intestinal fluid exhibits fissuring and collapses for reducing 
the possible accumulation of dosage forms in the gastrointestinal tract. 
EXAMPLE 4 
The above procedure of Example 3 is repeated with all the conditions as set 
forth, except that in this example the outside wall comprises ethyl 
cellulose. 
In summary, it will be readily appreciated that the present invention 
contributes to the art an unobvious dosage form manufactured as a drug 
delivery device possessing wide and practical application. While the 
invention has been described and pointed out in detail and with reference 
to operative embodiments thereof, it will be understood that those skilled 
in the art will appreciate that various changes, modifications, 
substitutions and omissions can be made without departing from the spirit 
of the invention. It is intended, therefore, that the invention embrace 
those equivalents within the scope of the claims which follow.