Delivery system comprising means for shielding a multiplicity of reservoirs in selected environment of use

A delivery system is disclosed for delivering an agent to a selected environment of use having a pH of greater than 3.5.

FIELD OF THE INVENTION 
This invention pertains to a novel system for delivering a beneficial drug 
in a selected environment of use. More particularly, the invention 
concerns a delivery system manufactured as a drug delivery device, and it 
comprises a multiplicity of tiny reservoirs containing a beneficial drug 
housed in a matrix formed of a pH sensitive material that releases the 
reservoirs in an environment having a pH of grater then 3.5. 
BACKGROUND OF THE INVENTION 
A critical and a pressing need exists presently for a delivery system that, 
(1) delivers a beneficial drug at a controlled rate and continuously in a 
biological environment having a pH of greater than 3.5 to 8.0 such as the 
intestine of an animal but, (2) does not deliver the drug in a biological 
environment having a pH of 1.0 to 3.5 inclusive, such as the stomach of an 
animal. The need arises because often it is contra-indicated and 
therapeutically undesirable to deliver many drugs in the stomach, and 
because often it is indicated and therapeutically desirable to deliver 
many drugs in the intestine. That is, some drugs do not lend themselves 
for delivery in the stomach, while some drugs lend themselves for delivery 
primarily in the intestine. 
For example, drugs where administration in the stomach should preferably be 
avoided include, (a) drugs that are digested or decomposed in the acidic 
environment of the stomach such as the antibiotics erythromycin and 
carbenicillium; (b) drugs that induce nausea and vomiting such as emetine, 
atabrine and diethylstilbestrol; and, (c) drugs that act as stomach 
irritants such as chloride and iron salts, and anti-inflammatory drugs 
like aspirin, flufenamic acid, and phenylbutazone. 
For example, drugs where administration in the intestine is preferred 
include, (d) intestinal antihelmitics such as bephenium hydroxynaphthoate, 
niclosamide, piperazine, thiabendazole and dichlorophen; (e) intestinal 
antibacterials such as methenamine, sulphasalazine and 
phthalylsulphthiazole; (f) antischistomals such as niridazoli; (g) 
antiprotozians such as dichlorophen; and, (h) drugs where it is desirable 
to dispense the medication in the intestine for initial absorption in the 
duodenum and jejunium, such as folic acid in the normal proximal jejunum. 
The above presentation clearly teaches both the necessity and the urgency 
for a unique delivery system that substantially avoids delivering a drug 
in the stomach, but which delivery system can administer a drug in a 
therapeutically effective amount in the intestine over time. It will be 
appreciated by those versed in the drug dispensing art in view of this 
presentation, that if a delivery system is provided that can fulfill these 
demands, such a delivery system would have a positive value and represent 
also a substantial contribution to the dispensing art. Likewise, it will 
be appreciated by those skilled in the art, that if a delivery system is 
made available for releasing drug at a controlled rate over time in the 
intestine for achieving therapeutic levels, such a delivery system would 
be clinically useful in the practice of medicine. 
OBJECTS OF THE INVENTION 
Accordingly, in view of the above presentation it is an immediate object of 
this invention to provide a novel and useful drug delivery system that 
satisfies the necessity and the urgency for a delivery system that 
administers drug in the intestine for obtaining better therapy in the 
management of health and disease. 
Another object of the present invention is to provide a drug delivery 
system having the combined effects of prompt initial drug delivery on 
entering into the intestine, and prolonged continuous administration of 
drug throughout the remainder of the intestine. 
Another object of the invention is to provide a delivery system for 
administering a drug in the intestine, which system is relatively 
economical in cost to manufacture, provides the physician with a 
dependable drug delivery means, and is well-adapted for practical and 
acceptable patient use. 
Yet another object of this invention is to provide a delivery system 
embodying physical-chemical properties that prevent release of drug in the 
stomach to reduce the risk of unwanted effects, and yet readily make 
available drug for absorption in the upper intestine and throughout the 
intestinal tract. 
Another object of this invention is to provide a delivery system 
manufactured as a drug delivery device that is simple in construction and 
exhibits all of the practical benefits of controlled and continuous 
administration of drug during its prolonged residency in the intestine for 
executing a therapeutic program. 
Still another object of the invention is to provide a delivery device 
comprising, (1) a matrix formed of a material that maintains its physical 
and chemical integrity in a first environment having a pH of 1.0 to 3.5 
inclusive, and (2) a multiplicity of drug reservoirs in the matrix, which 
drug reservoirs are shielded by the matrix from the first environment, and 
released by the matrix as the devices pass into a second environment 
having a pH of greater than 3.5 to 8.0. 
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.

DETAILED DESCRIPTION OF THE DRAWINGS 
Turning now to the drawings in detail, which are an example of a 
manufacturing procedure and a delivery system provided by the invention, 
and which examples are not to be construed as limiting, one example of the 
manufacturing procedure and the delivery system are seen in FIGS. 1 
through 5, considered together. 
Turning first to FIG. 1, there is seen the first manufacturing step in the 
assembly line leading to the delivery system of this invention. FIG. 1 
illustrates a mold 10 comprising a mold cavity 11 for receiving a 
multplicity of tiny reservoir 12 from reservoir feeding hopper 13. Hopper 
13 feeds a sufficient number of tiny reservoirs 12 into mold cavity 11 for 
filling said mold cavity 11. 
FIG. 2 illustrates another step in the manufacture of the delivery system. 
In FIG. 2, mold 10 is positioned at the assembly line station for 
receiving from polymer feeding hopper 14, a pH sensitive polymer 15 in 
liquid form, that fills mold cavity 11 and forms a solid polymer matrix 
for tiny reservoirs 12. 
FIG. 3 illustrates the delivery system 20 provided by the invention, and it 
comprises a matrix 21 that is adapted, shaped and sized for oral 
admittance into the gastrointestional tract of an animal, including a 
human. In FIG. 4, seen in opened section, matrix 21 comprises a solid, 
non-toxic polymer 15, represented by solid lines, which matrix 21 houses a 
multiplicity of tiny reservoirs 12 for the controlled delivery of a 
beneficial agent over time. The polymer material 15 forming matrix 21 is 
pH sensitive. That is, it is inert, or maintains its physical and chemical 
integrity at a pH up to and including 3.5, and at a pH of greater than 3.5 
it looses its physical and chemical integrity and releases tiny reservoirs 
12 for them to act both independently and collectively for delivering 
beneficial agent to the environment of use. 
In FIG. 5, individual tiny reservoirs 12 are seen in detail, some in 
cross-section, and they comprise a core of beneficial agent 22 surrounded 
by a wall 23 formed of a release rate controlling material. Tiny 
reservoirs 12 can have wall 23 formed of a single layer, or of more than 
one layer 24 comprising like or unlike release rate controlling materials. 
The layers comprising 23 and 24 can be of the same or different thickness. 
Additionally, the materials forming wall 23, 24, can be selected from 
materials that release agent 22 by different physical-chemical mechanisms. 
These mechansims include diffusion, osmosis, erosion, and metabolism in an 
environment having a pH of greater than 3.5. Various thicknesses of wall 
forming materials can be used as an aid for providing additional 
controlled release of beneficial agent. 
In operation, delivery system 20 operates by maintaining its integrity in 
an environment having a pH of from 1.0 to 3.5 inclusive, such as the 
stomach, and essentially does not release tiny reservoirs 12 in this 
environment. On passing into an environment having a pH of greater than 
3.5 to 8.0, such as the intestine, system 20 undergoes change by 
dissolving, dissolution, or the like, and releases tiny reservoirs 12 into 
the intestine. In the intestine, tiny reservoirs 12 deliver agent 22 over 
a prolonged period of time. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the practice of this invention, delivery system 20 
comprising matrix 21 is formed of a polymer 15 that keeps its physical and 
chemical integrity in a biological environment having a pH of from 1.0 to 
3.5 inclusive. Polymer 15 forming pH -sensitive matrix 21 is nontoxic, is 
physiologically inactive, and it does not adversely effect drug 22 and a 
host. Polymer 15 dissolves, disintegrates, degrades, hydrolyzes, 
solubilizes, is digested, or it undergoes like change in a biological 
environment at a pH greater than 3.5 to 8.0, thereby pH-releasing tiny 
timed reservoirs 12 into the biological environment. The product of 
polymer 15 produced on releasing reservoirs 12 is nontoxic, chemically 
inert, and physiologically inactive. In operation, matrix 21 keeps its 
integrity and provides structural support for reservoirs 12 during the 
period of time delivery system 20 is in the stomach and travels 
therethrough. Then, as delivery system 20 passes into the intestine, 
matrix 21 release reservoirs 12 for reservoirs 12 to delivery drug over 
the prolonged period of time reservoirs 12 travels through the intestine. 
Examples of matrix forming materials suitable for the present purpose 
include, (a) polymers having at least one acidic group that enables it to 
keep its integrity in a low pH environment, but releases the reservoirs in 
a higher pH environment, (b) polymers that undergo change in a higher pH 
environment by enzymes present in that environment, (c) polymer 
compositions comprising a polymer and another agent that promote at a 
higher pH the disintegration of the matrix, such as a polymer and a fat, 
fatty acid, wax and the like, and correspondingly the release of the 
reservoir, and (d) polymeric compositions comprising a polymer and agent 
such as a bile, cholesterol, or the like, that form complexes that 
disintegrate in a higher pH environment and concomitantly release the tiny 
timed reservoirs containing drug. 
Representative of polymers that keep their integrity at a pH of 1.0 to 3.5 
inclusive are polyacidic polymers having acid groups in an undissociated 
form in this pH range, such as vinyl derivatives of partially hydrolyzed 
styrene-maleic anhydride copolymer, methylmethacrylate-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 copolymers including 
maleic, citraconic or itaconic carboxylic acid anhydride, and the like. 
Representative of additional polymers that keep their integrity at a pH of 
1.0 to 3.5 inclusive, are cellulose carboxylic acid esters, cellulose 
carboxylic acid ethers, such as cellulose ethyl phthalate, cellulose 
acetate phthalate, starch acetate phthalate, amylose acetate phthalate, 
hydroxypropyl methylcellulose phthalate, alkali salts of cellulose acetate 
phthalate such as sodium salt cellulose acetate phthalate, alkaline earth 
salts of acidic cellulose esters such as 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. 
Representation of other polymers and polymer compositions comprising 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; and polymer 
compositions such as a mixture of hydroxypropyl methylcellulose phthalate 
and triacetate glycerol in a weight to weight ratio of 99 to 1, 
shellac-formalized gellatin composition, styrene-maleic acid copolymer 
dibutyl phthalate compositions, styrene-maleic acid polyvinyl acetate 
phthalate, shellac stearic acid, and the like. The matrix forming polymer 
compositions can contain small amounts, about 0.01 to 3 weight percent, or 
slightly more of a plasticizer such as esters of saturated and unsaturated 
fatty acids, of hydroxy carboxylic acids with ols such as alcohols and 
clycols, mono and draikyl phalates, and the like. Also, the polymeric 
composition can include a small amount, about 0.01 to 3 weight percent, or 
slightly more, of a filler such as carbon, talc, waxes, and the like. The 
matrix forming polymeric compositions can include also a binder such as 
sucrose, gelatin, gums, polyvinylpyrrolidone, polyethylene glycol, and the 
like. 
Matrix 21 comprising polymer 15 and tiny timed release reservoirs 12 can be 
made by conventional manufacturing methods. These methods include solution 
forming and compression forming processes. In the solution forming 
process, polymer 15 is mixed with a solvent and poured into mold cavity 11 
containing reservoirs 12. Then, the solvent is stripped from mold cavity 
11 by heat, vacuum, air blowing, or the like, causing polymer 15 to 
solidify yielding matrix 21 with reservoirs 12 releasably contained 
therein. Solvents operable for this purpose include methanol, ethanol, 
acetone, methanol-ethycelloslove, alcohol-acetone, methylene-chloride, 
methylene chloride-ethanol, methylene chloride-acetone; and the like. 
Examples of polymer 15 and a solvent combination are polyvinyl 
acetatephthalate and acetone, methylacrylate-methacrylic acid copolymer 
and acetone, polyacrylic acid ester and acetone, hydroxypropyl 
methylcellulose phthalate and acetone, hydroxypropyl methylcellulose 
phthalate and methanol-acetone, hydroxpropyl methycellulose phthalate and 
ethanol-acetate, cellulose acetate phthalate and acetone, cellulose 
acetate phthalate and methanol, 2-methyl-5-vinylpyridine 
methacrylate-methacrylic acid copolymer and ethanol, and the like. 
The compression forming process is carried out by charging mold cavity 11 
containing reservoirs 12 with polymer 15, or polymer composition 15 in 
powdered, particle, or like form, and then mold cavity 11 ingredients are 
compressed comparatively hard to form matrix 21 containing reservoirs 12. 
The term hard as used for the present purpose denotes a delivery system 
that keeps its physical and chemical integrity in the low pH range, 
thereby delaying release of the reservoirs and in vivo availability of the 
medicament until the delivery system passes into the higher pH biological 
environment. Matrix 21 can be formed by conventional compression machines 
such as Noyes, Stokes, Manesty machines, and the like. The pressure force 
applied to form the matrix-reservoir delivery system has a hardness of at 
least 4 kilograms, kg. More preferrably, the force is from 6 to 20 kg, and 
in a presently preferred embodiment, a force of 15 to 20 kg is applied 
over the surface of the ingredients in mold cavity 11. The force used is 
sufficient to minimize possible premature swelling of delivery system 20 
in the low pH environment and it substantially prevents the passage of a 
low pH fluid into the delivery system. It is also presently preferred 
embodiment, that reservoirs 12 be disposed in mold cavity 11 such that 
polymer 15 forms an exterior perimeter to lessen reservoirs 12 contact 
with the exterior of matrix 12 for essentially eliminating premature 
release of reservoirs 12 and delivery of medicament 22. Generally, 
delivery system 20 can have any operable shape corresponding to the shape 
of the die, such as square, rectangle, round, oblong and the like. The 
compression process used by the invention provides advantages, such as a 
solvent is not needed to compress the matrix, it provides a system having 
a uniform release of reservoirs in the higher pH environment, tacky 
powdered polymer can be used as an aid in compressing the matrix, and the 
like. 
Tiny reservoirs 12 used for the purpose of this invention provide for the 
controlled delivery of drug 22 over a prolonged period of time. Tiny 
reservoirs 12 comprise a drug 22 surrounded by a wall 23 of a drug release 
rate controlling material that delivers drug 22 in the biological 
environment having a pH of greater than 3.5 to 8.0. The prolonged period 
of time for the purpose of this invention corresponds to the period of 
time reservoirs 12 are in this environment. The materials forming wall 23 
are in a presently preferred proviso different materials than the 
materials forming matrix 21, and they can be selected from materials that 
release drug 22 by different physical-chemical mechanisms in a biological 
enivornment having a pH of greater than 3.5 to 8.0. These mechanisms 
include erosion, diffusion, osmosis, metabolism, and the like. Wall 23 can 
have various thicknesses and layers as an additional aid for providing 
timed release of drug 22. 
Wall 23 of tiny reservoirs 12 surrounding drug 22 can be a wall-forming 
composition consisting essentially of a fatty ester mixed with a wax, such 
as a triglyceryl ester selected from the group consisting of glyceryl 
distearate, glyceryl tristearate, glyceryl monostearate, glyceryl 
dipalmitate, glyceryl tripalmitate, glyceryl monolaurate, glyceryl 
didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl 
monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl 
monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl 
monodicenoate, glyceryl didecenoate and glyceryl tridecenoate. 
The was included in the wall forming composition is a member selected from 
the group consisting essentially of beeswax, cetyl palmitate, spermacetic 
wax, carnauba wax, cetyl myristate, cetyl palmitate, cetyl cerolate, 
stearyl palmitale, stearyl myristale, and lauryl laurate. 
The wall forming composition comprising the ester and the wax can be coated 
around the drug by using an organic solvent such as a member selected from 
the group consisting of carbon tetrachloride, chloroform, 
trichloroethylene, ether, benzene, ethyl acetate, methyl ethyl ketone, 
isopropyl alcohol, and the like. The fatty esters, waxes, solvents and 
procedures for making tiny reservoirs that slowly disintegrate and 
continuously provide drug over a period of 10 to 12 hours are disclosed in 
U.S. Pat. No. 2,793,979. 
Wall 23 of tiny reservoir 12 in another embodiment is formed of an osmotic 
wall forming material that releases drug 22 at a controlled rate by the 
process of osmotic bursting over time. Drug 22 in this embodiment is 
present in the form of an osmotic solute, such as a therapeutically 
acceptable salt, and it exhibits an osmotic pressure gradient across wall 
23 against an external fluid. The membrane material used to form wall 23 
is permeable to the passage of an external fluid and substantially 
impermeable to the passage of drug 22. Typical material includes a member 
selected from the group consisting of cellulose ester, cellulose ether, 
cellulose acylate, diacylate, cellulose triacylate, cellulose acetate, 
cellulose diacetate, cellulose triacetate, cellulose acetate having a 
degree of substitution, D.S. up to 1 and an acetyl content of 21%, 
cellulose diacetate having a D. S. of 1 to 2 and an acetyl content of 21 
to 35%, cellulose triacetate having a D. S. of 2 to 3 and an acetyl 
content of 35 to 44.8%, cellulose acetyl propionate, cellulose acetate 
butyrate, and the like. The osmotic wall can be coated around the drug in 
varying thicknesses by pan coating, spray-pan coating, Wurster fluid air 
suspension coating and the like. Wall 23 is formed using organic solents, 
including those mentioned above, and solvent systems such as methylene 
chloride-methanol, methylene chloride-acetone, methanol-acetone, ethylene 
dichloride-acetone, and the like. Osmotic wall forming procedures are 
disclosed in U.S. Pat. Nos. 2,799,241; 3,952,741; 4,014,334; and 
4,016,880. 
Wall 23 in another embodiment can be made of a drug release rate 
controlling material that releases drug by the process of diffusion. That 
is, drug 22 dissolves in wall 23 and passes through wall 23 at a 
controlled rate over time to the biological environment having a pH of 
greater than 3.5 to 8.0. Exemplary materials useful for forming a 
diffusional wall include ethylene-vinyl acetate copolymer, ethyl 
cellulose, polyethylene, cross-linked polyvinyl pyrrolidone, vinylidene 
chloride acrylonitrile copolymer, polypropylene, silicone, and the like. 
The wall can be applied by the techniques described above, and materials 
suitable for forming wall 23 are described in U.S. Pat. Nos. 3,938,515; 
3,948,262; and 4,014,335. 
Wall 23 in another embodiment can be made of a biolerodible material that 
bioerodes at a controlled rate and release drug 22 to a biological 
environment of use having a pH of greater than 3.5 to 8.0 Bioerodible 
materials useful for forming wall 15 include polyvalent alkali mobile 
cross-linked polyelectrolytes, polycarboxylic acid, polyesters, 
polyamides, polyimides, polylactic acid, polyglycolic acid, 
polyorthoesters, and polycarbonate polymers that erode in the pH of 
greater than 3.5 to 8.0. The polymers and the procedures for forming wall 
23 are disclosed in U.S. Pat. Nos. 3,811,444; 3,867,519; 3,888,975; 
3,971,367; 3,993,057; and 4,138,344. 
In the specification and the accompanying claims the term drug denotes 
pharmacologically beneficial substances that are absorbed in an intestinal 
environment by one or more of the following transport mechanisms: active 
transport, passive transport, pore transport, or facilitated transport to 
produce a local or systemic effect in animals. The term animals as used 
herein includes warm-blooded mammals such as humans. The beneficial drug 
that can be delivered in a biological environment having a pH greater than 
3.5 to 8.0 are drugs that act on the central nervous system, depressants, 
hypnotics, sedatives, psychic energizers, tranquilizers, muscle relaxants, 
antiparkinson, analgesics, anti-inflammatory, hormonal, contraceptives, 
sympathomimetics, diuretcis, antiparasites, neoplastics, hypoglycemics, 
electrolytes, cardiovascular, anthelmintics, and the like. 
Exemplary drugs that are administered in an environment having a pH greater 
than 3.0 to 8 include hycanthone, aminophylline, aminosalicyclic acid, 
chymotrypsin, sulfoxone sodium, diethylstilbestrol, erythromycin estolate, 
erthromycin, orenzyme, carbomycin, riboflavin, thiamine, vitamin D.sub.2, 
vitamin D.sub.3, vitamin B.sub.12, nitrogen mustard derivatives, 
phenylbutazone, acetysalicylic acid, helmintheasis xanthones, 
helminthiasis thioxanthones, narcotics morphine and codeine, derivatives 
of pyrimedines including 5-fluorouracil and 5-bromouracil, quaternaly 
ammonium compounds including benzomethamine, oxyphenonium, hexamethonium, 
and tubocurarine, atropine, and the like. The beneficial drugs are known 
in the art in Pharmaceutical Sciences, by Remington, 1980, published by 
Mack Publishing Co.; Physicians' Desk Reference, 36 Edition, 1982, 
published by Medical Economics Co.; and, Medicinal Chemistry, 3rd Edition, 
Vol. 1 and 2, by Burger, published by Wiley-Interscience Co. 
Drug 22 can be present in tiny reservoirs 12 in various forms, such as 
uncharged molecules, molecular complexes, as therapuetically 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 a water soluble derviative 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 present in a tiny timed reservoir generally is about 10 
ng to 25 mg. For some drug, a slightly higher amount may be present in the 
reservoir. The number of tine timed reservoirs present in a delivery 
system is about 10 to 1000, and preferably for an oral delivery system 
about 100 to 150. The tiny reservoirs comprising the wall and the inner 
drug core have a diameter of about 100 microns, and in a presently 
preferred embodiment a diameter of about 2000 microns. For oral use, the 
delivery system comprising the matrix and the tiny reservoirs homogenously 
or heterogenously housed therein, can have conventional shapes such as 
round, oval and the like. The delivery system can have a diameter of 4 mm 
to 15 mm, and the like. 
The following examples will serve to further illustrate the invention. A 
delivery system manufactured and sized, shaped and adapted as an orally 
administrable tablet containing tiny reservoirs of a sympathomimetic drug 
is prepared as follows: first, powdered drug is mixed with sucrose and the 
blend passed through a 15 to 30 mesh screen to yield a multiplicity of 
cores of drug. Then, a drug release rate wall forming composition 
comprising 85% glycerol monostearate and 15% beeswax in warm carbon 
tetrachloride is spayed over the cores in a revolving coating pan until a 
wall is formed that surrounds individually and separately each drug core. 
Next, the coating solvent is stripped from the tiny reservoirs, and a 
series of mold cavities are charged with 50 tiny reservoirs and 200 mg of 
a matrix forming pH sensitive powdered polymer. The matrix forming 
polymer, slightly tacky cellulose acetate phthalate, is a different 
polymer than the polymer composition used to form the wall of the 
reservoirs. Finally, the filled mold cavity is pressed under a pressure of 
18 kg to yield the delivery system. 
Another drug delivery system is provided by coating a drug core, for 
example, procainamide hydrochloride, in a fluid air suspension with a wall 
forming compositions of ethyl cellulose in ethanol to surround the drug 
core with ethyl cellulose, to yield the tiny reservoirs. After the solvent 
is vacuum stripped from the tiny reservoirs, the reservoirs are blended 
with ground tacky shellac and pressed into an oral tablet. 
The aboce manufacture can be repeated by replacing the ethyl cellulose and 
ethanol with cellulose acetate having an acetyl content of 32% and 
methylene chloride-methanol solvent and then dispersing the tiny reservirs 
in a pH releasable matrix comprising sticky polyvinylacetate phthylate; 
or, by applying a bioerodible wall of poly(2,2-dioxo-trans-1,4-cyclohexane 
dimethylene tetrahydrofuran) around the drug core. The latter polymer is 
applied by heating the polymer to 80.degree.-90.degree. C., and then 
dispersing a multiplicity of tiny reservoirs in matrix forming 
polyvinylacetate phthalate. 
In another example, a delivery system is made by first preparing sustained 
intestinal release tiny reservoirs by blending 400 ml of ethyl 
cellulose-water, 70:30% solution, with 375 g of aminophylline, 150 g of 
mannitol and 475 g of magnesium stearate, and the blend kneaded and passed 
through an extrusion granulation machine. After drying at 
115.degree.-120.degree. F., the reservoir forming drug cores are passed 
through a 20 mesh screen and then coated with a wall of ethyl cellulose in 
an air suspension machine to yield the tiny reservoirs. The number of 
coats surrounding the drug core is variable, usually 1 to 10 separate 
coats are used for the present purpose. Next, a multiplicity of reservoirs 
are blended with very slightly aqueous moist granulated sodium 
hydroxypropyl methylcellulose phthalate and the blend fed into the mold 
cavity of a tablet compressing machine. Then, the blend is compressed 
under a pressure head of at least 16 kg/cm.sup.2 and under vacuum to yield 
the delivery system. 
Other drug delivery systems are made by spraying nonpareil cores with an 
erodible, non-toxic adhesive and then dusting with drug. The drug-coated 
core is coated with an appropriate number of non-toxic intestinal drug 
release rate polymer composition to yield the tiny reservoirs. The number 
of polymer composition coating is variable, usually at least 1 to 20 
separate coats. Finally, the tiny reservoirs are housed in a pH sensitive 
reservoir. The tiny reservoirs also can be made from a core carbohydrate, 
such as sucrose, dusted with a mixture of talc, starch and galactose, 
moistened with distilled or deconized water, then dusted with the desired 
medicinal, such as the antibiotic erythromycin, and then coated with a 
reservoir wall forming polymer composition. The reservoirs are dried and 
then suspended in a solid matrix selected from the group consisting of a 
polymer composition of at least two wall forming members such as shellac 
and ammoniated shellac, polyvinyllactate, phthalate, a blend of 
polyvinyllactate phthalate and polyvinyllactate phthalate, and the like. 
It will be appreciated by those versed in the delivery art the present 
invention advances the state-of-the-art by providing (a) a delivery system 
comprising tiny reservoirs that release drug in an environment having a pH 
greater than 3.5, which tiny reservoirs do not require an additional coat 
that prevents their releasing drug in an environment having a pH up to 
3.5, inclusive, as they are individually housed in an environment 
protective matrix; (b) by providing a delivery system that substantially 
protects the drug from the digestive processes of the stomach; (c) by 
providing a delivery system that substantially eliminates irritating a 
mucous membranes of the stomach by shielding the drug from contact with 
the membranes; (d) by providing a delivery system that delivers drugs to 
the intestinal tract in their therapeutically active forms at a controlled 
and constant rate of delivery throughout the intestinal tract during the 
period of time the tiny reservoir traverse the intenstine, and 
correspondingly establishing in an animal recipient drug blood drug levels 
exhibiting a decrease in peak and valleys of drug which may lead to ing a 
decrease in peak and valleys of drug which may lead to unwanted results; 
and (e) by providing a delivery system that embodies delayed onset of 
delivery at a later time with the capability of dispersing drug delivered 
over the intestinal tract to enhance drug absorption and/or local 
treatment of the color. 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.