Controlled release formulations coated with aqueous dispersions of acrylic polymers

A stable solid controlled release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer includes a substrate including an active agent selected from the group consisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting and sanitizing agent, a cleansing agent, a fragrance agent and a fertilizing agent, overcoated with an aqueous dispersion of the plasticized water-insoluble acrylic polymer. The formulation provides a stable dissolution of the active agent which is unchanged after exposure to accelerated storage conditions.

BACKGROUND OF THE INVENTION 
An important aspect of the manufacture, regulatory review and approval of 
all dosage forms concerns their stability over extended periods of time. 
The stability data obtained with regard to a particular dosage form 
directly affects its shelf-life. The stability of a pharmaceutical dosage 
form is related to maintaining its physical, chemical, microbiological, 
therapeutic, and toxicological properties when stored, i.e., in a 
particular container and environment. Stability study requirements are 
covered, e.g., in the Good Manufacturing Practices (GMPs), the U.S.P., as 
well as in the regulatory requirements of the country where approval to 
market a dosage form is being sought. In the United States, a request to 
test, and eventually market, a drug or a drug formulation may be made via 
a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA) 
or an Investigational New Drug Applications (IND). 
The agents used in sustained release dosage formulations often present 
special problems with regard to their physical stability during storage. 
For example, waxes which have been used in such formulations are known to 
undergo physical alterations on prolonged standing, thus precautions are 
taken to stabilize them at the time of manufacture or to prevent the 
change from occurring. Fats and waxy materials when used in purified 
states are known to crystallize in unstable forms, causing-unpredictable 
variations in availability rates during stability testing at the time of 
manufacture and during later storage. 
It is known that certain strategies can be undertaken to obtain stabilized 
controlled release formulations in many cases, such as insuring that the 
individual agents are in a stable form before they are incorporated into 
the product, and that processing does not change this condition, retarding 
the instability by including additional additives, and inducing the 
individual agents of the dosage form to reach a stable state before the 
product is finally completed. 
It is also recognized that the moisture content of the product can also 
influence the stability of the product. Changes in the hydration level of 
a polymeric film, such as the ethyl celluloses, can alter the rate of 
water permeation and drug availability. Also, binders such as acacia are 
known to become less soluble when exposed to moisture and heat. However, 
moisture content of a product can be controlled fairly successfully by 
controls in the processing method and proper packaging of the product. 
Hydrophobic polymers such as certain cellulose derivatives, zein, acrylic 
resins, waxes, higher aliphatic alcohols, and polylactic and polyglycolic 
acids have been used in the prior art to develop controlled release dosage 
forms. Methods of using these polymers to develop controlled release 
dosage forms such as tablets, capsules, suppositories, spheroids, beads or 
microspheres include incorporating these agents into a controlled release 
matrix or using certain of these agents in a controlled release coating of 
the dosage form. It is known in the prior art that hydrophobic coatings 
can be applied either from a solution, suspension or dry. Since most of 
the polymers used in controlled release coatings have a low solubility in 
water, they are usually applied by dissolving the polymer in an organic 
solvent and spraying the solution onto the individual drug forms (such as 
beads or tablets) and evaporating off the solvent. 
Aqueous dispersions of hydrophobic polymers have been used in the prior art 
to coat pharmaceutical dosage forms for aesthetic reasons such as film 
coating tablets or beads or for taste-masking. However, these dosage forms 
are used for immediate release administration of the active drug contained 
in the dosage form. 
The use of organic solvents in the preparation of hydrophobic coatings is 
considered undesirable because of inherent problems with regard to 
flammability, carcinogenicity, environmental concerns, cost, and safety in 
general. It is considered very desirable in the art, however, to provide a 
controlled release coating derived from aqueous dispersions of a 
hydrophobic material, such as an acrylic polymer. 
While many formulations have been experimentally prepared which rely upon a 
hydrophobic coating derived from an aqueous dispersion to provide 
controlled release of an active agent, such formulations have not proven 
to be commercially viable because of stability problems. Aqueous polymeric 
dispersions have been used to produce stable controlled release dosage 
forms, but this has only been possible by other methods such as 
incorporation of the same into the matrix of the dosage form, rather than 
via the use of a coating of the aqueous polymeric dispersion to obtain 
retardant properties. 
When coating using aqueous polymeric dispersions to obtain a desired 
release profile of the active agent(s) over several hours or longer, it is 
known in the art that the dissolution release profile changes on ageing, 
e.g. when the final coated product is stored for a period of time, during 
which time it may be exposed to elevated temperature and/or humidity above 
ambient conditions. 
This was recently demonstrated by Munday, et al., Drug Devel. and Indus. 
Phar., 17 (15) 2135-2143 (1991), which reported the effect of storing 
theophylline mini-tablets film coated with ethyl cellulose with PEG (2:1 
ratio; total coating =3% w/w), ethyl cellulose with Eudragit.RTM. L (2:1 
ratio; total coating =3% w/w); and Eudragit.RTM. RL (amount of coating 
=1.5% w/w) at varying temperatures and relative humidities upon the rate 
of drug release. Samples were subjected to isothermal storage at 
28.degree. C., 35.degree. C. and 45.degree. C. with the relative humidity 
(RH) maintained between 55-60%, under cyclic conditions of 45.degree. C. 
at 55% RH for 24 hours, then at 28.degree. C. and 20% RH for 24 hours, and 
then at 5.degree. C. and 10% RH for 24 hours, after which the cycle was 
repeated, and alternating conditions every 24 hours between 45.degree. C. 
and 55% RH and 28.degree. C. and 0% RH. The aging process brought about by 
storage under the above stress conditions impeded dissolution, 
irrespective of the nature of the polymeric film. The greatest reduction 
in release rate was said to occur in the first 21 days (isothermal 
storage) after coating. 
While this instability problem is known not to exist when the polymers are 
applied from organic solvent solution, it has not been possible to obtain 
a controlled release formulation utilizing coatings prepared from such 
aqueous acrylic polymer dispersions which is stable under various storage 
conditions. 
In particular, it is known that controlled release coatings of commercially 
available acrylic polymers such as those sold under the tradename 
Eudragit.RTM. by Rohm Pharma GmbH are not stable when cured according to 
recommended curing conditions of 45.degree. C. for 2 hours. 
OBJECTS AND SUMMARY OF THE INVENTION 
It is therefore an object of the present invention to provide a controlled 
release formulation of a substrate comprising an active agent, e.g. a 
therapeutically active agent, a disinfecting agent, a cleansing agent, a 
sanitizing agent and a fertilizing agent, coated with an aqueous 
dispersion of a hydrophobic acrylic polymer such that there is a stable 
dissolution or other release profile of the active agent when placed in an 
environment of use, despite exposure to a variety of storage conditions, 
including accelerated storage conditions. 
It is another object of the present invention to provide a controlled 
release formulation comprising a plurality of inert beads comprising an 
active agent, and a controlled release tablet comprising a core containing 
an active agent, the beads or tablet core being coated with an aqueous 
dispersion of a hydrophobic polymer and providing a reproducible, stable 
dissolution despite exposure to accelerated storage conditions, as well as 
a method of preparing the same. 
Still another object of the present invention is to provide a controlled 
release formulation comprising a substrate containing an active agent 
coated with an aqueous dispersion of a hydrophobic polymer which upon 
dissolution in-vitro provides a band range, when comparing the dissolution 
profile of the formulation after exposure to a variety of storage 
conditions including "stressed" or accelerated storage conditions, which 
is not wider than about 15% of total active agent released at any point of 
time during the dissolution. 
A further object of the present invention is to provide a controlled 
release formulation wherein the controlled release is caused by a coating 
on the formulation of an aqueous dispersion of a hydrophobic polymer such 
as an acrylic polymer which coating provides a stable dissolution of an 
active agent contained in the formulation, despite exposure to accelerated 
storage conditions such that the dissolution would be deemed acceptable by 
a governmental regulatory agency such as the U.S. FDA for purposes of 
according expiration dating. 
These objects and others have been accomplished by the present invention, 
which relates in part to a controlled release formulation comprising a 
substrate comprising an active agent in an amount sufficient to provide a 
desired effect in an environment of use, the substrate being coated with 
an aqueous dispersion of plasticized pharmaceutically acceptable 
hydrophobic acrylic polymer in an amount sufficient to obtain a controlled 
release of said active agent when said formulation is exposed to an 
environmental fluid, and cured at a temperature greater than the glass 
transition temperature of the aqueous dispersion of plasticized acrylic 
polymer for a sufficient period of time until a curing endpoint is reached 
at which the coated substrate provides a stable dissolution of the active 
agent which is unchanged after exposure to accelerated storage conditions. 
The endpoint may be determined, e.g., by comparing the dissolution profile 
of the formulation immediately after curing to the dissolution profile of 
the formulation after exposure to accelerated storage conditions such as 
one to three months at a temperature of 37.degree. C. and at a relative 
humidity of 80%, or at a temperature of 40.degree. C. and at a relative 
humidity of 75%. In certain preferred embodiments, the substrate is coated 
to a weight gain from about 2% to about 25%. 
In other preferred embodiments, the coated substrate when subjected to 
in-vitro dissolution, releases said active agent in amounts which do not 
vary at any time point along the dissolution curve by more than about 15% 
of the total amount of active agent released, when compared to the 
in-vitro dissolution of said coated substrate after curing. 
In yet other embodiments of the invention, the cured formulation provides a 
stabilized dissolution of said active agent which is unchanged after 
exposure to accelerated storage conditions, the stabilized dissolution 
being deemed appropriate by the United States Food & Drug Administration 
for the purpose of according expiration dating for said formulation. 
Other preferred embodiments relate to controlled release dosage formulation 
comprising a substrate coated with an effective amount of an aqueous 
dispersion of acrylic polymer to obtain a controlled release of an active 
agent which formulation, after exposure to accelerated storage conditions, 
releases an amount of therapeutically active agent which does not vary at 
any given dissolution time point by more than about 20% of the total 
amount of therapeutically active agent released, when compared to in-vitro 
dissolution conducted prior to storage. The acrylic polymer preferably has 
a permeability which is unaffected by the pH conditions prevailing in the 
gastrointestinal tract. 
In other embodiments, the coated substrate, upon in-vitro dissolution 
testing, provides a band range after exposure to accelerated storage 
conditions which is not wider than about 20% at any point of time when 
compared to the dissolution profile prior to exposure to the accelerated 
storage conditions. 
The active agent may be chosen for a wide variety of uses, including but 
not limited to systemically active therapeutic agents, locally active 
therapeutic agents, disinfectants, cleansing agents, fragrances, 
fertilizers, deodorants, dyes, animal repellents, insect repellents, 
pesticides, herbicides, fungicides, and plant growth stimulants. 
The present invention is further related to a solid controlled release oral 
dosage formulation, comprising a substrate containing a systemically 
active therapeutic agent in an amount sufficient to provide a desired 
therapeutic effect when said formulation is orally administered. The 
substrate is coated with an aqueous dispersion of plasticized acrylic 
polymer and cured at a temperature greater than the glass transition 
temperature of the aqueous dispersion of plasticized acrylic polymer for a 
period of time sufficient to obtain a controlled release of said active 
agent when measured by the USP Paddle or Basket Method at 100 rpm at 900 
ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 0% 
to about 42.5% (by wt) active agent released after 1 hour, from about 5% 
to about 60% (by wt) active agent released after 2 hours, from about 15% 
to about 75% (by wt) active agent released after 4 hours, and from about 
20% to about 90% (by wt) active agent released after 8 hours. The coated 
substrate has a stable release when comparing the rate of release of the 
active agent after exposing the coated substrate to accelerated 
conditions, to the release rate obtained immediately after curing. The 
dosage form preferably provides a therapeutic effect for about 24 hours. 
The present invention further relates to a method of preparing the dosage 
form. 
The present invention is also related to a method for obtaining a 
controlled release formulation of an active agent, comprising preparing a 
solid substrate comprising an active agent, coating the substrate with a 
sufficient amount an aqueous dispersion of plasticized acrylic polymer to 
obtain a predetermined controlled release of the active agent when the 
coated substrate is exposed to an environmental fluid, and curing the 
coated substrate at a temperature greater than the glass transition 
temperature of the aqueous dispersion of plasticized acrylic polymer until 
a curing endpoint is reached at which said coated substrate provides a 
stabilized dissolution of said active agent which is unchanged after 
exposure to accelerated storage conditions. 
The present invention is further related to a method of treating a patient 
with an oral solid dosage form described above. In this method, present 
invention further comprises administering the oral solid dosage form 
comprising the cured, coated substrate to the patient to thereby obtain 
the desired therapeutic effect for about 12 to about 24 hours or more. In 
especially preferred embodiments, the oral solid dosage forms of the 
present invention provide a desired therapeutic effect for about 24 hours. 
In certain preferred embodiments of the present invention, the hydrophobic 
acrylic polymer is comprised of copolymerizates of acrylic and methacrylic 
acid esters having a permeability which is unaffected by the pH conditions 
prevailing in the gastrointestinal tract. Preferably, these 
copolymerizates further include a low content of quaternary ammonium 
groups, which occur as salts and are responsible for the permeability of 
the lacquer substances. 
The present invention provides many benefits over prior art coatings, 
including, but not limited to, avoidance of organic solvents which have 
inherent safety concerns (flammability, carcinogenicity, environmental 
concerns, cost, safety in general), and extended stability which may 
result in extended shelf life and expiration dating.

DETAILED DESCRIPTION 
The aqueous dispersions of hydrophobic acrylic polymers used as coatings in 
the present invention may be used to coat substrates such as tablets, 
spheroids (or beads), microspheres, seeds, pellets, ion-exchange resin 
beads, and other multi-particulate systems in order to obtain a desired 
controlled release of the active agent. Granules, spheroids, or pellets, 
etc., prepared in accordance with the present invention can be presented 
in a capsule or in any other suitable dosage form. The tablets of the 
present invention may be any suitable shape, such as round, oval, 
biconcave, hemispherical, any polygonal shape such as square, rectangular, 
and pentagonal, and the like. 
In order to obtain a controlled release formulation, it is usually 
necessary to overcoat the substrate comprising the active agent with a 
sufficient amount of the aqueous dispersion of hydrophobic acrylic polymer 
to obtain a weight gain level from about 2 to about 25 percent, although 
the overcoat may be lesser or greater depending upon the physical 
properties of the active agent and the desired release rate, the inclusion 
of plasticizer in the aqueous dispersion and the manner of incorporation 
of the same, for example. In certain embodiments of the invention, the 
controlled release coatings may be applied to the substrate up to, e.g., a 
50% weight gain. 
The cured, coated substrates of the present invention provide a stable 
dissolution profile (e.g., release of the active agent in the environment 
of use) when stored for extended periods of time at room temperature and 
ambient humidity (e.g., long term (real time) testing), and when tested 
under accelerated storage conditions. 
The terms "stable dissolution profile" and "curing endpoint" are defined 
for purposes of the present invention as meaning that the cured, coated 
substrate reproducibly provides a release of the active agent when placed 
in an environment of use which is unchanged, even after exposing the 
cured, coated substrate to accelerated storage conditions. Those skilled 
in the art will recognize that by "unchanged" it is meant that any change 
in the release of the active agent from the cured, coated formulation 
would be deemed insignificant in terms of the desired effect. For 
pharmaceutical formulations, stability is evaluated by, e.g, a regulatory 
agency such as the Food & Drug Administration (FDA) in the U.S., for the 
purpose of according an expiration date for the formulation. 
By the phrase "accelerated storage conditions" it is meant, e.g., storage 
conditions of elevated temperature and/or elevated relative humidity. 
Preferably, the phrase "accelerated storage conditions" refers to storage 
conditions to which the final drug formulation is subjected for the 
purpose of obtaining regulatory approval (e.g., FDA approval in the U.S.) 
and an expiration date. 
The term "expiration date" is defined for purposes of the present invention 
as the date designating the time during which a packaged batch of the 
product (e.g., the cured, coated substrate) is expected to remain within 
specification if stored under defined conditions, and after which it 
should not be used. 
By "environmental fluid", it is meant that the formulation is placed in an 
aqueous solution (e.g., in-vitro dissolution), in simulated gastric fluid 
(e.g., in accordance with the USP Basket Method (i.e., 37.degree. C., 100 
RPM, first hour 700 ml gastric fluid with or without enzymes at pH 1.2, 
then changed to 900 ml at pH 7.5), or in gastrointestinal fluid (in-vivo). 
The term "band range" or "band width" for purposes of the present invention 
is defined as the difference in in-vitro dissolution measurements of the 
controlled release formulations when comparing the dissolution profile 
(curve) obtained by the formulation upon completion of the manufacturing 
of the coated product (prior to storage) and the dissolution profile 
obtained after the coated product is exposed to accelerated storage 
conditions, expressed as the total (absolute) change in percent of the 
active agent released from the coated product at any dissolution time 
point along the dissolution curves. 
In general, the length of the studies and the storage test conditions 
required by regulatory agencies such as the FDA for pharmaceutical 
formulations are sufficient to cover storage, shipment, and subsequent 
use. Allowable storage test conditions may vary depending upon the 
particulars of the product. For example, temperature sensitive drug 
substances should be stored under an alternative, lower temperature 
condition, which is then deemed to be the long term testing storage 
temperature. In such cases, it is generally accepted that the accelerated 
testing should be carried out at a temperature at least 15.degree. C. 
above this designated long term storage temperature, together with 
appropriate relative humidity conditions for that temperature. 
A generally accepted accelerated test employed in FDA guidelines relates to 
the storage of a drug product (e.g., in its container and package) at 80% 
Relative Humidity (RH) and 37.degree. C. (1985 FDA guidelines). If the 
product holds up for, e.g., three months under these conditions (chemical 
stability, dissolution, and physical characteristics), then the drug 
product will be accorded, e.g., a two year expiration date. This 
accelerated test is also now also considered to be acceptable if conducted 
at 75% RH and 40.degree. C. (FDA 1987 guidelines). It has recently been 
proposed that long-term storage testing be conducted for pharmaceutical 
formulations at 25.degree. C..+-.2.degree. C. at not less than 60% 
RH.+-.5% for a minimum time period of 12 months. It has been further 
proposed that accelerated testing be conducted for pharmaceutical 
formulations at 40.degree. C..+-.2.degree. C. at 75% RH.+-.5% for a 
minimum time period of 6 months. All of the above-mentioned accelerated 
testing criteria and others are deemed equivalent for purposes of the 
present invention, with regard to the determination of stability and the 
determination of the curing endpoint. All of the above-mentioned 
accelerated testing conditions, as well as others known to those skilled 
in the art, provide an acceptable basis for determining the curing 
(stability) endpoint of the controlled release formulations of the present 
invention. 
The controlled release coatings of the present invention comprise aqueous 
dispersions of hydrophobic (water-insoluble) acrylic polymers. In certain 
preferred embodiments, the hydrophobic acrylic polymer coatings of the 
present invention have a solubility and permeability independent of the pH 
of the fluid present in the environment of use. In the case of oral solid 
dosage forms, the hydrophobic acrylic polymers of the present invention 
have a solubility and permeability independent of physiological pH values. 
Hydrophobic acrylic polymers which may be used in the formulations of the 
present invention are derived from acrylic acid or derivatives thereof. 
Acrylic acid derivatives include, for example, the esters of acrylic acid 
and methacrylic acid, and the alkyl esters of acrylic acid and methacrylic 
acid. In certain preferred embodiments, the alkyl esters of acrylic acid 
and methacrylic acid have from about 1 to about 8 carbon atoms in the 
alkyl group. The monomers which may be used in the polymer coatings of the 
present invention also include styrene and its homologs, vinyl esters such 
as vinyl acetate, and vinyl chloride. Generally, monomers forming 
hydrophobic water-insoluble polymers are nonionic. The term "nonionic 
monomers" for purposes of the present invention is meant to include not 
only monomers which have no ionic groups (such as alkali metal carboxylate 
or sulfonate or tertammonium groups) in the molecule, but also monomers 
which are unable to form such groups with bases or acids. In many cases, 
the composition of the hydrophobic acrylic polymer coating may include 
other monomers. 
One skilled in the art will appreciate that the hardness and extensibility 
of the coating film and the lowest temperature at which film formation 
from the aqueous dispersion is possible are influenced by the particular 
monomers included in the hydrophobic acrylic polymer used in the present 
invention. Lower alkyl esters of methacrylic acid are known to form 
relatively harder homopolymers, which acrylic acid esters and the higher 
alkyl esters of methacrylic acid provide relatively softer homopolymers. 
Alkyl groups having greater than 4carbon atoms or aryl groups have a 
hydrophobizing effect and thereby reduce the swelling capacity and 
diffusion permeability. 
In certain preferred embodiments of the present invention, the acrylic 
polymer also includes one or more polymerizable permeability-enhancing 
compounds which will allow the active agent enclosed within the coating to 
be released at a desired diffusion rate, regardless of the prevailing pH 
value. In the case of oral solid dosage forms, the permeability-enhancing 
compound allows the active agent to be released at the same diffusion rate 
in each region of the digestive (gastrointestinal) tract (regardless of 
pH) during passage of the dosage form therethrough; after having been 
substantially completely extracted, the coatings of the present invention 
are eliminated without decomposing. 
In certain preferred embodiments, the permeability-enhancing compound 
comprises at least one polymerizable quaternary ammonium compound. Such 
compounds are strong bases which are present as stable salts in a wide pH 
range, e.g., throughout the entire physiological pH region, and are easily 
water soluble. The nature, and particularly the amount, of the quaternary 
ammonium compound present in the copolymeric agent are important factors 
affecting diffusion behavior. 
Suitable polymerizable quaternary ammonium compounds which may be used in 
the coatings of the present invention generally correspond to the general 
formula 
##STR1## 
wherein R is hydrogen or methyl; A is oxygen or NH; B is a linear or 
branched alkyl or is an alicyclic hydrocarbon, preferably having from 
about 2 to about 8 carbon atoms; R.sub.1, R.sub.2 and R.sub.3, taken 
alone, are the same or different alkyl or aralkyl, and more particularly 
are lower alkyl having from about 1 to about 4 carbon atoms, or are 
benzyl, or R1 and R2, taken together with the quaternary nitrogen atom, 
are piperidinium or morpholinium; and 
X.sup..crclbar. is a cation, preferably of an inorganic acid, particularly 
chloride, sulfate, or methosulfate. 
Particular examples of polymerizable quaternary ammonium compounds include 
quaternized aminoalkyl esters and aminoalkyl amides of acrylic acid and 
methacrylic acid, for example .beta.-methacryl-oxyethyl-trimethyl-ammonium 
methosulfate, .beta.-acryloxypropyl-trimethyl-ammonium chloride, and 
trimethylaminomethylmethacrylamide methosulfate. The quaternary ammonium 
atom can also be part of a heterocycle, as in 
methacryloxyethylmethyl-morpholinium chloride or the corresponding 
piperidinium salt, or it can be joined to an acrylic acid group or a 
methacrylic acid group by way of a group containing hetero atoms, such as 
a polyglycol ether group. Further suitable polymerizable quaternary 
ammonium compounds include quaternized vinyl-substituted nitrogen 
heterocycles such as methyl-vinyl pyridinium salts, vinyl esters of 
quaternized amino carboxylic acids, styryltrialkyl ammonium salts, and the 
like. 
Other polymerizable quaternary ammonium compounds useful in the present 
invention are acryl- and methacryl-oxyethyltrimethylammonium chloride and 
methosulfate, benzyldimethylammoniumethylmethacrylate chloride, 
diethylmethylammoniumethyl-acrylate and -methacrylate methosulfate, 
N-trimethylammoniumpropylmethacrylamide chloride, and 
N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride. 
Further information concerning suitable hydrophobic acrylic polymers may be 
obtained from U.S. Pat. Nos. 3,520,970 and 4,737,357 (both assigned to 
Rohm G.m.b.H), both of which are hereby incorporated by reference. 
One skilled in the art will appreciate that other polymerizabilable 
permeability-enhancing compounds may be substituted in the present 
invention for the quaternary ammonium compounds mentioned above. Such 
additional polymerizable permeability-enhancing compounds are contemplated 
to be within the scope of the appended claims. 
In certain preferred embodiments, the hydrophobic acrylic polymer used in 
the coatings of the present invention comprises copolymerizates of acrylic 
and methacrylic acid esters with a low content of quaternary ammonium 
groups. Such copolymerizates are often referred to as ammonio methacrylate 
copolymers, and are commercially available from Rohm Pharma AG, e.g., 
under the tradename Eudragit.RTM.. Ammonio methacrylate copolymers are 
described in NF XVII as fully polymerized copolymers of acrylic and 
methacrylic acid esters with a low content of quaternary ammonium groups. 
In certain especially preferred embodiments of the present invention, the 
acrylic coating is derived from a mixture of two acrylic resin lacquers 
used in the form of aqueous dispersions, commercially available from Rohm 
Pharma under the Tradename Eudragit.RTM. RL 30 D and Eudragit.RTM. RS 30 
D, respectively. Eudragit.RTM. RL 30 D and Eudragit.RTM. RS 30 D are 
copolymers of acrylic and methacrylic esters with a low content of 
quaternary ammonium groups, the molar ratio of ammonium groups to the 
remaining neutral (meth)acrylic esters being 1:20 in Eudragit.RTM. RL 30 D 
and 1:40 in Eudragit.RTM. RS 30 D. The mean molecular weight is about 
150,000. The code designations refer to the permeability properties of 
these agents, RL for high permeability and RS for low permeability. 
Eudragit.RTM. RL/RS mixtures are insoluble in water and in digestive 
fluids. However, coatings formed from the same are swellable and permeable 
in aqueous solutions and digestive fluids. 
The Eudragit.RTM. RL/RS dispersions of the present invention may be mixed 
together in any desired ratio in order to ultimately obtain a controlled 
release formulation having a desirable dissolution profile. Desirable 
controlled release formulations may be obtained, for instance, from a 
retardant coating derived from 100% Eudragit.RTM. RL, 50% Eudragit.RTM. RL 
and 50% Eudragit.RTM. RS, and 10% Eudragit.RTM. RL:Eudragit.RTM. 90% RS, 
and 100% Eudragit.RTM. RS. 
The hydrophilic acrylic polymers used in the present invention may be 
manufactured in any manner known to those skilled in the art, including 
methods such as bulk polymerization in the presence of a free 
radical-forming initiator dissolved in the monomer mixture, or solution or 
precipitation polymerization in an organic solvent, with the polymer thus 
formed thereafter being isolated from the solvent. 
The hydrophobic acrylic polymer coatings of the present invention may also 
include hydrophilic monomers having a solubility which is not dependent on 
pH. Examples are acrylamide and methacrylamide, hydroxy alkyl esters of 
acrylic acid and methacrylic acid, and vinyl pyrrolidone. Such materials 
if used, may be included in small amounts up to 20 percent by weight of 
the copolymer. Also, small amounts of ionic monomers, such as acrylic acid 
or methacrylic acid or amino monomers on which the quaternized monomers 
are based, may also be included. 
In other embodiments of the present invention, the hydrophobic acrylic 
polymer coating further includes a polymer whose permeability is pH 
dependent, such as anionic polymers synthesized from methacrylic acid and 
methacrylic acid methyl ester. Such polymers are commercially available, 
e.g., from Rohm Pharma GmbH under the tradename Eudragit.RTM. L and 
Eudragit.RTM. S. The ratio of free carboxyl groups to the esters is said 
to be 1:1 in Eudragit.RTM. L and 1:2 in Eudragit.RTM. S. Eudragit.RTM. L 
is insoluble in acids and pure water, but becomes increasingly permeable 
above pH 5.0. Eudragit.RTM. S is similar, except that it becomes 
increasingly permeable above pH 7. The hydrophobic acrylic polymer 
coatings may also include a polymer which is cationic in character based 
on dimethylaminoethyl methacrylate and neutral methacrylic acid esters 
(such as Eudragit.RTM. E, commercially available from Rohm Pharma). The 
hydrophobic acrylic polymer coatings of the present invention may further 
include a neutral copolymer based on poly (meth)acrylates, such as 
Eudragit.RTM. NE (NE=neutral ester), commercially available from Rohm 
Pharma. Eudragit.RTM. NE 30D lacquer films are insoluble in water and 
digestive fluids, but permeable and swellable. 
The dissolution profile of any given formulation in accordance with the 
present invention may by altered by changing the relative amounts of 
different acrylic resin lacquers included in the coating. Also, by 
changing the molar ratio of polymerizable permeability-enhancing agent 
(e.g., the quaternary ammonium compounds) to the neutral (meth)acrylic 
esters, the permeability properties (and thus the dissolution profile) of 
the resultant coating can be modified. 
The release of the active agent from the controlled release formulation of 
the present invention can be further influenced, i.e., adjusted to a 
desired rate, by the addition of one or more pore-formers which can be 
inorganic or organic, and include materials that can be dissolved, 
extracted or leached from the coating in the environment of use. Upon 
exposure to fluids in the environment of use, the pore-formers are, e.g., 
dissolved, and channels and pores are formed that fill with the 
environmental fluid. 
For example, the pore-formers may comprise one or more water-soluble 
hydrophilic polymers in order to modify the release characteristics of the 
formulation. Examples of suitable hydrophilic polymers include 
hydroxypropylmethylcellulose, cellulose ethers and protein-derived 
materials. Of these polymers, the cellulose ethers, especially 
hydroxyalkylcelluloses and carboxyalkylcelluloses, are preferred. Also, 
synthetic water-soluble polymers may be used, such as 
polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene 
oxide, etc., water-soluble polydextrose, saccharides and polysaccharides, 
such as pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose, 
mannose, galactose, sorbitol and the like In certain preferred embodiments 
of the present invention, the hydrophilic polymer comprises 
hydroxypropylmethylcellulose. 
Other examples of pore-formers include alkali metal salts such as lithium 
carbonate, sodium chloride, sodium bromide, potassium chloride, potassium 
sulfate, potassium phosphate, sodium acetate, sodium citrate, and the 
like. The pore-forming solids may also be polymers which are soluble in 
the environment of use, such as Carbowaxes.RTM., Carbopol.RTM., and the 
like. The pore-formers embrace diols, polyols, polyhydric alcohols, 
polyalkylene glycols, polyglycols, poly(a-w)alkylenediols, and the like. 
Semipermeable polymers may also be incorporated in the controlled release 
coating as a pore-former to change the release characteristics of the 
formulation. Such semipermeable polymers include, for example, cellulose 
acylates, acetates, and other semipermeable polymers such as those 
described in U.S. Pat. No. 4,285,987 (hereby incorporated by reference), 
as well as the selectively permeable polymers formed by the 
coprecipitation of a polycation and a polyanion as disclosed in U.S. Pat. 
Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142 (hereby 
incorporated by reference). 
Other pore-formers which may be useful in the formulations of the present 
invention include starch, modified starch, and starch derivatives, gums, 
including but not limited to xanthan gum, alginic acid, other alginates, 
bentonite, veegum, agar, guar, locust bean gum, gum arabic, quince 
psyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth, 
scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linked 
polyvinylpyrrolidone, ion-exchange resins, such as potassium 
polymethacrylate, carrageenan, kappa-carrageenan, lambdacarrageenan, gum 
karaya, biosynthetic gum, etc. Other pore-formers include materials useful 
for making microporous lamina in the environment of use, such as 
polycarbonates comprised of linear polyesters of carbonic acid in which 
carbonate groups reoccur in the polymer chain, microporous materials such 
as bisphenol, a microporous poly(vinylchloride), microporous polyamides, 
microporous modacrylic copolymers, microporous styrene-acrylic and its 
copolymers, porous polysulfones, halogenated poly(vinylidene), 
polychloroethers, acetal polymers, polyesters prepared by esterification 
of a dicarboxylic acid or anhydride with an alkylene polyol, 
poly(alkylenesulfides), phenolics, polyesters, asymmetric porous polymers, 
cross-linked olefin polymers, hydrophilic microporous homopolymers, 
copolymers or interpolymers having a reduced bulk density, and other 
similar materials, poly(urethane), cross-linked chain-extended 
poly(urethane), poly(imides), poly(benzimidazoles), collodion, regenerated 
proteins, semi-solid cross-linked poly(vinylpyrrolidone). 
In general, the amount of pore-former included in the controlled release 
coatings of the present invention may be from about 0.1% to about 80%, by 
weight, relative to the combined weight of hydrophobic acrylic polymer and 
pore-former. 
The controlled release coatings of the present invention may also include 
an exit means comprising at least one passageway, orifice, or the like. 
The passageway may be formed by such methods as those disclosed in U.S. 
Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are 
hereby incorporated by reference). The passageway can have any shape such 
as round, triangular, square, elliptical, irregular, etc. The passageway 
may be included instead of, or in addition to, the inclusion of 
permeability-enhancing compounds, hydrophilic monomers, pH-sensitive 
polymers, and/or pore-formers, in order to obtain a release of the active 
agent(s) included in the formulation. 
In one embodiment of the present invention, the hydrophobic polymer 
included in the aqueous polymer coating dispersion is water-insoluble 
(such as a copolymer of acrylic and methacrylic acid esters without the 
inclusion of any quaternary ammonium compound), and the release of the 
active agent is controlled substantially only via the presence of one or 
more passageways through the coating. 
An example of a suitable controlled release formulation pursuant to the 
present invention will provide a dissolution rate in vitro of the dosage 
form, when measured by the USP Paddle or Basket Method at 100 rpm in 900 
ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C., is from about 
0 to about 42.5% (by wt) therapeutically active agent released after 1 
hour, from about 25 from about 55% (by wt) released after 2 hours, between 
45 and 75% (by wt) released after 4 hours and greater than about 55% (by 
wt) released after 6 hours, for, e.g., a 12 hour formulation (administered 
twice daily). Another example of a suitable controlled release formulation 
pursuant to the present invention is one which will provide a dissolution 
rate in vitro of the dosage form, when measured by the USP Paddle or 
Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) 
at 37.degree. C. from about 0% to about 42.5% (by wt) active agent 
released after 1 hour, from about 5% to about 60% (by wt) active agent 
released after 2 hours, from about 15% to about 75% (by wt) active agent 
released after 4 hours, and from about 20% to about 90% (by wt) active 
agent released after 8 hours, for e.g., a 24 hour formulation 
(administered once daily). These examples of acceptable dissolution rates 
are directed to certain preferred embodiments of the present invention 
where the formulations are oral solid dosage forms, and are not intended 
to be limiting in any manner whatsoever. 
The coating formulations of the present invention should be capable of 
producing a strong, continuous film that is smooth and elegant, capable of 
supporting pigments and other coating additives, non-toxic, inert, and 
tack-free. 
It is preferred that the acrylic coatings used in the present invention 
include an effective amount of a suitable plasticizing agent, as it has 
been found that the use of a plasticizer further improves the physical 
properties of the film. For example, the use of a plasticizer may improve 
the film elasticity and lower the film-forming temperature of the 
dispersion. The plasticization of the acrylic resin may be accomplished 
either by so-called "internal plasticization" and "external 
plasticization." 
Internal plasticization usually pertains directly to molecular 
modifications of the polymer during its manufacture, e.g., by 
copolymerization, such as altering and/or substituting functional groups, 
controlling the number of side chains, or controlling the length of the 
polymer. Such techniques are usually not performed by the formulator of 
the coating solution. 
External plasticization involves the addition of a material to a film 
solution so that the requisite changes in film properties of the dry film 
can be achieved. 
The suitability of a plasticizer depends on its affinity or solvating power 
for the polymer and its effectiveness at interfering with polymer-polymer 
attachments. Such activity imparts the desired flexibility by relieving 
molecular rigidity. Generally, the amount of plasticizer included in a 
coating solution is based on the concentration of the film-former, e.g., 
most often from about 1 to about 50 percent by weight of the film-former. 
Concentration of the plasticizer, however, can only be properly determined 
after careful experimentation with the particular coating solution and 
method of application. 
Most preferably, about 20% plasticizer is included in the aqueous 
dispersion of acrylic polymer. 
An important parameter in the determination of a suitable plasticizer for a 
polymer is related to the glass transition temperature (Tg) of the 
polymer. The glass transition temperature is related to the temperature or 
temperature range where there is a fundamental change in the physical 
properties of the polymer. This change does not reflect a change in state, 
but rather a change in the macromolecular mobility of the polymer. Below 
the Tg, the polymer chain mobility is severely restricted. Thus, for a 
given polymer, if its Tg is above room temperature, the polymer will 
behave as a glass, being hard, non-pliable and rather brittle, properties 
which could be somewhat restrictive in film coating since the coated 
dosage form may be subjected to a certain amount of external stress. 
Incorporation of suitable plasticizers into the polymer matrix effectively 
reduces the Tg, so that under ambient conditions the films are softer, 
more pliable and often stronger, and thus better able to resist mechanical 
stress. 
Other aspects of suitable plasticizers include the ability of the 
plasticizer to act as a good "swelling agent" for the acrylic resin. 
Examples of suitable plasticizers for the acrylic polymers of the present 
invention include, but are not limited to citric acid esters such as 
triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 
1,2-propylene glycol. Other plasticizers which have proved to be suitable 
for enhancing the elasticity of the films formed from acrylic films such 
as Eudragit.RTM. RL/RS lacquer solutions include polyethylene glycols, 
propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl 
citrate is an especially preferred plasticizer for the aqueous dispersions 
of acrylic polymers of the present invention. 
It has further been found that the addition of a small amount of talc 
reduces the tendency of the aqueous dispersion to stick during processing, 
and acts as a polishing agent. 
The dissolution profile of the ultimate product may also be modified, for 
example, by increasing or decreasing the thickness of the retardant 
coating, by altering the manner in which the plasticizer is added, by 
varying the amount of plasticizer relative to acrylic resin, and/or by 
altering other aspects of the method of manufacture, for example. 
In one preferred embodiment of the present invention, the controlled 
release dosage form comprises pharmaceutically acceptable beads (e.g., 
spheroids) containing the active ingredient coated with a controlled 
release coating. The term spheroid is known in the pharmaceutical art and 
means, e.g., a spherical granule having a diameter of between 0.2 mm and 
2.5 mm especially between 0.5 mm and 2 mm. A suitable commercially 
available example of such beads are nu pariel 18/20 beads. 
A plurality of the cured, coated (stabilized) controlled release beads may 
thereafter be placed in a gelatin capsule in an amount sufficient to 
provide an effective controlled release dose when ingested and contacted 
by gastric fluid. 
When the dispersion of acrylic resin is used to coat inert pharmaceutical 
beads such as nu pariel 18/20 mesh beads, a plurality of the resultant 
stabilized solid controlled release beads may thereafter be placed in a 
gelatin capsule in an amount sufficient to provide an effective controlled 
release dose when ingested and contacted by gastric fluid. In this 
embodiment, beads coated with a therapeutically active agent are prepared, 
e.g., by dissolving the therapeutically active agent in water and then 
spraying the solution onto a substrate, for example, nu pariel 18/20 mesh 
beads, using a Wurster insert. Optionally, additional ingredients are also 
added prior to coating the beads in order to assist the active ingredient 
binding to the beads, and/or to color the solution, etc. For example, a 
product which includes hydroxypropyl methylcellulose, etc. with or without 
colorant may be added to the solution and the solution mixed (e.g., for 
about 1 hour) prior to application of the same onto the beads. The 
resultant coated substrate, in this example beads, may then be optionally 
overcoated with a barrier agent, to separate the therapeutically active 
agent from the acrylic coating. An example of a suitable barrier agent is 
one which comprises hydroxypropyl methylcellulose. However, any 
film-former known in the art may be used. It is preferred that the barrier 
agent does not affect the dissolution rate of the final product. 
The beads comprising the active agent (with optional protective coating) 
may then be overcoated with the acrylic polymer. The dispersion of acrylic 
polymer preferably further includes an effective amount of plasticizer, 
e.g. triethyl citrate. Pre-formulated dispersions of acrylic resins, such 
as various commercially available forms of Eudragit.RTM., such as 
Eudragit.RTM. RS30D and Eudragit.RTM. RL 30D. 
The coating solutions of the present invention preferably contain, in 
addition to the film-former, plasticizer, and solvent system (i.e., 
water), a colorant to provide elegance and product distinction. Color may 
be added to the solution of the therapeutically active agent instead, or 
in addition to the overcoat. Suitable ingredients for providing color to 
the formulation include titanium dioxide and color pigments, such as iron 
oxide pigments. The incorporation of pigments, may, however, increase the 
retard effect of the coating. Alternatively, any suitable method of 
providing color to the formulations of the present invention may be used. 
The plasticized coating of acrylic polymer (with optional permeability 
enhancing compounds and/or pore-formers) may be applied onto the substrate 
comprising the therapeutically active agent by spraying using any suitable 
spray equipment known in the art. In a preferred method, a Wurster 
fluidized-bed system is used in which an air jet, injected from 
underneath, fluidizes the core material and effects drying while the 
acrylic polymer coating is sprayed on. A sufficient amount of the coating 
to obtain a predetermined controlled release of the therapeutically active 
agent when said coated substrate is exposed to aqueous solutions, e.g. 
gastric fluid, is preferably applied, taking into account the physical 
characteristics of the therapeutically active agent, the manner of 
incorporation of the plasticizer, etc. After coating with acrylic resin, a 
further overcoat of a film-former, such as Opadry.RTM., is optionally 
applied to the beads. This overcoat is provided, if at all, in order to 
substantially reduce agglomeration of the beads. 
Next, the coated beads, tablets, etc. are cured in order to obtain a 
stabilized release rate of the therapeutically active agent. 
Traditionally, curing has been carried out for Eudragit.RTM. coated 
formulations, if at all, via a fluid bed at 45.degree. C. for 2 hours 
after application. Such a standard curing is recommended by Rohm Pharma 
because it is above the glass transition temperature (Tg) of Eudragit.RTM. 
RS 30 D plasticized with triethylcitrate at a 20% level of solids. This 
recommended curing does not stabilize the dissolution profile of the 
formulation upon storage, as will be demonstrated by the examples set 
forth herein. 
The curing step pursuant to the present invention is accomplished by 
subjecting the coated substrate, e.g., beads, to a temperature greater 
than the Tg of the coating formulation and continuing the curing until an 
endpoint is reached at which the coated formulation attains a dissolution 
profile which is substantially unaffected by exposure to storage 
conditions of elevated temperature and/or humidity. Generally, the curing 
time is about 24 hours or more, and the curing temperature may be, for 
example, about 45.degree. C. It has further been discovered in the present 
invention that it is not necessary to subject the coated substrate to 
humidity levels above ambient conditions during the curing step in order 
to achieve a stabilized end product. 
One possible mechanism for the change in the dissolution profile of prior 
art products cured by the standard methods is that these products continue 
to cure during storage, and may never reach a stabilized end-point at 
which the product provides a substantially constant dissolution profile. 
In contrast, the cured products of the present invention provide a release 
rate of the therapeutically active agent which is substantially unaffected 
during storage by elevations in temperature and humidity. 
In preferred embodiments of the present invention, the stabilized product 
is obtained by subjecting the coated substrate to oven curing at a 
temperature above the Tg of the plasticized acrylic polymer for the 
required time period, the optimum values for temperature and time for the 
particular formulation being determined experimentally. 
In certain embodiments of the present invention, the stabilized product is 
obtained via an oven curing conducted at a temperature of about 45.degree. 
C. for a time period from about 24 to about 48 hours. In certain 
embodiments, it may be preferable to cure the product for, e.g., 36 hours. 
In certain preferred embodiments, the product is cured for about 48 hours. 
It is also contemplated herein that certain products coated with the 
controlled release coating of the present invention may require a curing 
time longer than 48 hours, e.g. 60 hours or more. One skilled in the art 
will recognize that curing conditions will be affected by the particular 
drug incorporated in the formulation, as well as by the thickness of the 
controlled release coating, and the size of the substrate (e.g., beads as 
compared to tablets). 
It is especially contemplated that the time period needed for curing to an 
endpoint as described above may actually be longer or shorter than the 
time periods mentioned above. Such curing times which achieve the intended 
result of a stabilized formulation are considered to be encompassed by the 
appended claims. Additionally, it will be appreciated by those skilled in 
the art that it may be possible to cure the aqueous dispersion coated 
substrates of the present invention in other manners in order to reach the 
endpoint at which the coated substrate provides a stable dissolution 
profile. Additional curing methods (such as sonication) which achieve the 
intended result of a stabilized formulation are also considered to be 
encompassed by the appended claims. 
The curing endpoint may be determined by comparing the dissolution profile 
of the cured, coated substrate (e.g., the "formulation") immediately after 
curing (hereinafter referred to as "the initial dissolution profile") to 
the dissolution profile of the formulation after exposure to accelerated 
storage conditions. Generally, the curing endpoint may be determined by 
comparing the dissolution profile of the formulation after exposure to 
accelerated storage conditions of, e.g., 37.degree. C./80% RH or 
40.degree. C./75% RH for a time period of one month to the initial 
dissolution profile. However, the curing endpoint may be further confirmed 
by continuing to expose the cured, coated formulation to accelerated 
storage conditions for a further period of time and comparing the 
dissolution profile of the formulation after further exposure of, e.g., 
two months and/or three months, to the initial dissolution profile 
obtained. 
In certain preferred embodiments of the present invention in which the 
cured coated substrate is a pharmaceutical formulation, the curing 
endpoint is attained when the data points plotted along a graph of the 
dissolution curve obtained after, e.g., exposure to accelerated conditions 
of 1-3 months, show a release of the active agent which does not vary at 
any given time point by more than about 15% of the total amount of active 
agent released when compared to in-vitro dissolution conducted prior to 
storage. Such a difference in the in-vitro dissolution curves, referred to 
in the art as a "band range" or a "band width" of, e.g., 15%. In general, 
where the in-vitro dissolution prior to storage and after exposure to 
accelerated conditions varies by not more than, e.g., about 20% of the 
total amount of active agent released, the formulation is considered 
acceptable when considered by governmental regulatory agencies such as the 
U.S. FDA for stability concerns and expiration dating. Acceptable band 
ranges are determined by the FDA on a case-by-case basis, and any band 
range for a particular pharmaceutical which would be deemed acceptable by 
such a governmental regulatory agency would be considered to fall within 
the appended claims. In preferred embodiments, the aforementioned band 
range is not more than 10% of the total amount of active agent released. 
In more preferred embodiments, the band range is not more than 7% of the 
total amount of active agent released. In the appended Examples, the band 
range is often less than 5%. 
When the controlled release coating of the present invention is to be 
applied to tablets, the tablet core (e.g. the substrate) may comprise the 
active agent along with any pharmaceutically accepted inert pharmaceutical 
filler (diluent) material, including but not limited to sucrose, dextrose, 
lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, mixtures 
thereof and the like. Also, an effective amount of any generally accepted 
pharmaceutical lubricant, including the calcium or magnesium soaps may be 
added to the above-mentioned agents of the excipient prior to compression 
of the tablet core agents. Most preferred is magnesium stearate in an 
amount of about 0.2-5% by weight of the solid dosage form. 
In certain embodiments of the present invention, the coated substrate 
includes an additional dose of active agent included in either the 
controlled release coating comprising the aqueous dispersion of 
hydrophobic polymer, or in an additional overcoating coated on the outer 
surface of the controlled release coating. This may be desired when, for 
example, a loading dose of a therapeutically active agent is needed to 
provide therapeutically effective blood levels of the active agent when 
the formulation is first exposed to gastric fluid. In such cases, a 
further protective coating (e.g., of HPMC) may be included to separate the 
immediate release coating layer from the controlled release coating layer. 
The active agent(s) included in the controlled release formulations of the 
present invention include systemically active therapeutic agents, locally 
active therapeutic agents, disinfecting agents, chemical impregnants, 
cleansing agents, deodorants, fragrances, dyes, animal repellents, insect 
repellents, a fertilizing agents, pesticides, herbicides, fungicides, and 
plant growth stimulants, and the like. 
A wide variety of therapeutically active agents can be used in conjunction 
with the present invention. The therapeutically active agents (e.g. 
pharmaceutical agents) which may be used in the compositions of the 
present invention include both water soluble and water insoluble drugs. 
Examples of such therapeutically active agents include antihistamines 
(e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and 
dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, 
morphine, dihydromorphone, oxycodone, etc.), non-steroidal 
anti-inflammatory agents (e.g., naproxyn, diclofenac, indomethacin, 
ibuprofen, sulindac), anti-emetics (e.g., metoclopramide), anti-epileptics 
(e.g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., 
nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents 
and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g. 
theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine), 
antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, 
bendrofluazide), anti-hypotensives (e.g., propranolol, clonidine), 
antihypertensives (e.g, clonidine, methyldopa), bronchodilators (e.g., 
albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), 
antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, 
psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, 
laxatives, vitamins, stimulants (including appetite suppressants such as 
phenylpropanolamine), as well as salts, hydrates, and solvates of the 
same. The above list is not meant to be exclusive. 
In certain preferred embodiments, the therapeutically active agent 
comprises hydromorphone, oxycodone, dihydrocodeine, codeine, 
dihydromorphine, morphine, buprenorphine, salts, hydrates and solvates of 
any of the foregoing, mixtures of any of the foregoing, and the like. 
In another preferred embodiment of the present invention, the active agent 
is a locally active therapeutic agent and the environment of use may be, 
e.g., the gastrointestinal tract, or body cavities such as the oral 
cavity, periodontal pockets, surgical wounds, the rectum or vagina. 
The locally active pharmaceutical agent(s) include antifungal agents (e.g., 
amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.), 
antibiotic agents (penicillins, cephalosporins, erythromycin, 
tetracycline, aminoglycosides, etc.), antiviral agents (e.g, acyclovir, 
idoxuridine, etc.), breath fresheners (e.g. chlorophyll), antitussive 
agents (e.g., dextromethorphan hydrochloride), anti-cariogenic compounds 
(e.g. metallic salts of fluoride, sodium monofluorophosphate, stannous 
fluoride, amine fluorides), analgesic agents (e.g., methylsalicylate, 
salicylic acid, etc.), local anesthetics (e.g., benzocaine), oral 
antiseptics (e.g., chlorhexidine and salts thereof, hexylresorcinol, 
dequalinium chloride, cetylpyridinium chloride), anti-flammatory agents 
(e.g., dexamethasone, betamethasone, prednisone, prednisolone, 
triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol), 
antiplaque agents (e.g, chlorhexidine and salts thereof, octenidine, and 
mixtures of thymol, menthol, methysalicylate, eucalyptol), acidity 
reducing agents (e.g., buffering agents such as potassium phosphate 
dibasic, calcium carbonate, sodium bicarbonate, sodium and potassium 
hydroxide, etc.), and tooth desensitizers (e.g., potassium nitrate). This 
list is not meant to be exclusive. 
In another preferred embodiment of the present invention, the active agent 
is disinfecting agent, e.g. a chlorine compound such as calcium 
hypochlorite, and the environment of use is a surrounding body of water, 
e.g. a recreational pool. 
In still another preferred embodiment of the present invention, the active 
agent comprises at least one of a cleansing agent, a germicide, a 
deodorant, a surfactant, a fragrance, a perfume, a sanitizer, and/or a 
dye, and the environment of use is an aqueous solution, e.g. a urinal or 
toilet bowl. 
In yet another preferred embodiment of the present invention, the active 
agent is a chemical impregnant, e.g. fertilizer, animal repellents, insect 
repellents, pesticides, herbicides, fungicides, plant growth stimulants, 
and the environment of use is, e.g., anywhere around the home, e.g. soil, 
trees etc. The fertilizer may be, for example, a nitrogen containing 
compound such as urea, urea formaldehyde composites, potassium nitrate, 
potassium sulfate, potassium chloride, ammonium nitrate, ammonium sulfate, 
monoammonium phosphate, dibasic ammonium phosphate. ammoniated 
super-phosphoric acid, micronutrient ingredients such as trace elements of 
iron, zinc, manganese, copper, boron, molybdenum, and mixtures of any of 
the foregoing. The fertilizer may be, e.g., in granular form. In these 
embodiments, the thickness of the controlled release coating will depend 
upon, among other things, the desired rate and overall time period for 
release of an effective amount of the active agent. In some circumstances 
where a relatively long time period of efficacy is desired, the substrate 
may be coated to a relatively high weight gain of, e.g., up to 50% or 
more. In other situations, it may be desirable to obtain the desired 
efficacy by utilizing coated substrates which are coated to different 
weight gains, or which include different components of the coating, so 
that a desired proportion of the coated substrates provide a release of 
active agent which is faster relative to other of the coated substrates, 
thereby providing an overall release of active agent which is within the 
desired effective levels for an even longer extended period of time. 
For example, when the coated substrate is a coated chlorine tablet for 
combatting bacterial and algaecidal contamination of swimming pools and 
the like, the substrate may comprise commercial grade calcium 
hypochlorite, with or without trichloroisocyanuric acid, sodium 
dichlorocyanurate, lithium hypochlorite, powdered lime, and/or the like. 
For example, the substrate may comprise about 98.5% commercial grade 
calcium hypochlorite and about 1.5% powdered lime, by weight. The 
substrate may also comprise commercial granular calcium hypochlorite, up 
to 20% by weight chloride of lime, and 1% zinc stearate having an 
available chlorine percentage of about 69% and a mass of about 57 g and a 
diameter of about 40 mm, as described in U.S. Pat. No. 4,192,763, hereby 
incorporated by reference. The substrate is then coated with the aqueous 
dispersion of plasticized hydrophobic polymer to a desired weight gain, 
and the coated tablet is then cured in accordance with the present 
invention until an endpoint is reached at which the cured coated tablet 
provides a reproducibly stable dissolution profile. 
When the active agent comprises a composition suitable for cleaning and 
preventing the staining of toilet bowls, the substrate may include a 
well-known disinfectant such as calcium hypochlorite and/or 
trichloroisocyanuric acid. The active agent may alternatively comprise an 
alkali metal salt of dichloroisocyanuric acid and a chloride salt such as 
calcium chloride and barium chloride, such as that which is described in 
U.S. Pat. No. 4,654,341, hereby incorporated by reference. 
One possible example of such a product might include a substrate comprising 
0.5-5% fragrance, 1-10% dye, 10-40% surfactant (which may be nonionic, 
cationic, anionic or zwitterion surfactants), and other optional 
components such as germicides, disinfectants, processing aids, and other 
commonly included ingredients known to those skilled in the art. Such 
active agents may be incorporated into a substrate comprising a tablet, 
along with other well-known ingredients such as detergents, surfactants, 
perfumes, dyes, and any necessary fillers. 
The substrate may be alternatively comprised of a pellet which is prepared 
by homogenously mixing together, e.g., 1 g of azure blue dye 65% (dye 
commercially available from Hilton David), 1 g Pluronic F-127 (a nonionic 
surfactant comprising the condensation products of ethylene oxide with the 
product resulting from the reaction of propylene oxide and ethylene 
diamine; commercially available from BASF-Wyandote Chemicals), 38 g 
Carbowax 8000 (a solid polyethylene glycol, molecular weight 8000; 
commercially available from Union Carbide), and 40 g Kemamide U (a 
oleylamide surfactant; commercially available from Witco) and an optional 
fragrance (e.g., 0.5% by weight citrus pine fragrance), and thereafter 
processing the above ingredients into a pellet by conventional methods 
such as noodling, plodding, extruding and cutting and stamping the mass to 
form the pellets. Optionally, the pellets may also include a suitable 
amount of an inorganic salt to cause the pellet to settle to the tank 
bottom, and one or more binding agents such as guar gum. The pellet is 
then coated with the aqueous dispersion of plasticized hydrophobic polymer 
to a weight gain from about 2 to about 30 percent, depending upon the 
desired rate of dissolution, and the coated pellet is then cured in 
accordance with the present invention until an endpoint is reached at 
which the cured coated pellet provides a reproducibly stable dissolution 
profile. 
Another example of a substrate useful for the treatment of the flush water 
of toilets is one which comprises an iodophor such as povidone iodine, as 
described in U.S. Pat. No. 5,043,090, hereby incorporated by reference. 
When the substrate comprises a fragrance, the fragrance may be any 
conventional commercially available perfume oil, e.g., volatile compounds 
including esters, ethers aldehydes, alcohols, unsaturated hydrocarbons, 
terpenes, and other ingredients which are well known in the art. Their 
type and compatibility is limited only by their compatibility and 
desirability, as may be determinable by those skilled in the art. 
When the active agent comprises a composition suitable for use as a 
fertilizer, the active agent may comprise granular urea which is coated 
with the aqueous dispersion of plasticized hydrophobic polymer to a weight 
gain from about 2 to about 30 percent and then cured in accordance with 
the present invention. In urea pill production, urea at 70% solids 
concentration in water is heated to remove substantially all of the water. 
The molten urea is then injected as droplets to an air cooling tower where 
crystalline urea is formed as a hard pill or bead, which is then coated 
and cured in accordance with the present invention. 
When the substrate comprises plant food formulations, the substrate can be 
pelleted, ball-shaped, particulate, or in stick form, and may additionally 
contain growth promoting substances such as gibberellic acid along with 
soil fungistats such as formaldehyde and paraformaldehyde, etc. 
A split-screen Scanning Electron Micrograph (SEM) of a theophylline bead 
coated with an aqueous dispersion of Eudragit in accordance with the 
present invention prior to curing shows the distinct particles of acrylic 
polymers on the coating. Due to, e.g. cracks or pores in the coating, the 
environmental fluid can pass through to the underlying core where the 
active agent is found. 
A split-screen SEM of the same theophylline bead taken after the bead has 
been cured in an oven at 45.degree. C. for a time period of 48 hours shows 
apparent morphological changes to the coating on the surface of the bead. 
This curing is believed to play a significant role in the stabilization of 
the dissolution profile of the coated substrate. 
When the controlled release coating of the present invention is to be 
applied to tablets, the tablet core (e.g. the substrate) may comprise the 
active agent along with any pharmaceutically accepted inert pharmaceutical 
filler (diluent) material, including but not limited to sucrose, dextrose, 
lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, mixtures 
thereof and the like. Also, an effective amount of any generally accepted 
pharmaceutical lubricant, including the calcium or magnesium soaps may be 
added to the above-mentioned ingredients of the excipient prior to 
compression of the tablet core ingredients. Most preferred is magnesium 
stearate in an amount of about 0.2-5% by weight of the solid dosage form. 
Tablets overcoated with a sufficient amount of the coating of acrylic resin 
to achieve a controlled release formulation pursuant to the present may be 
prepared and cured in similar fashion as explained above with regard to 
the preparation of beads. One skilled in the art will recognize that 
necessary curing conditions with regard to the particular elevated 
temperature, elevated humidity and time ranges necessary to obtain a 
stabilized product, will depend upon the particular formulation. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The following examples illustrate various aspects of the present invention. 
They are not to be construed to limit the claims in any manner whatsoever. 
EXAMPLE 1 
Preparation of Hydromorphone Beads 
Hydromorphone beads were prepared by dissolving hydromorphone HCl in water, 
adding Opadry.RTM. Y-5-1442, light pink (a product commercially available 
from Coloron, West Point, Pa. which contains hydroxypropyl methylcellulose 
(HPMC), hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and 
D&C Red No. 30 Aluminum Lake), 20% w/w, and mixing for about 1 hour, and 
then spraying onto nu pariel 18/20 mesh beads using a Wurster insert. The 
resultant preparation had the formula set forth in Table 1 below: 
TABLE 1 
______________________________________ 
Ingredients Percent (by wt) 
Amt/Unit (mg) 
______________________________________ 
Hydromorphone HCl 
5.0% 4.0 mg 
Nu Pariel 18/20 
92.5% 74.0 mg 
Opadry .RTM. 
Lt. Pink Y-5-1442 
2.5% 2.0 mg 
100.0% 80.0 mg 
______________________________________ 
EXAMPLE 2 
Retardant Coating--No Curing Step 
In Example 2, hydromorphone beads prepared in accordance with Example 1 
were overcoated with Eudragit.RTM. RS 30D to a 5% weight gain as set forth 
in Table 2 below. No terminal drying was conducted. 
TABLE 2 
______________________________________ 
Percent 
Ingredients (by wt) Amt/Unit (mg) 
______________________________________ 
Hydromorphone beads 
92.59 80 
Eudragit .RTM. RS30D 
4.63 4 
Citroflex 2 0.93 0.8 
(triethyl citrate) 
Talc 1.85 
Purified water qs 
100 86.4 
______________________________________ 
The hydromorphone beads were tested for initial dissolution, and then 
stored for one month under accelerated conditions of 37.degree. C./80%RH 
(RH=relative humidity). After one month, the beads were found to have 
agglomerated. 
Dissolution tests were carried out via the USP Basket Method, 37.degree. 
C., 100 RPM, first hour 700 ml gastric fluid at pH 1.2, then changed to 
900 ml at 7.5. The dissolution was conducted by placing an open capsule 
containing an appropriate weight of beads into a vessel. The results are 
set forth in Table 3 below: 
TABLE 3 
__________________________________________________________________________ 
Hydromorphone HCl 12 mg Controlled Released Capsules 
Stability Performance Data 
Hydromor- 
Average 
phone Fill Wt 
Time HCl (mg) 1 hr 
2 hr 
4 hr 
8 hr 
12 hr 
18 hr 
24 hr 
__________________________________________________________________________ 
Initial 12.34 259.2 
1.5 
5.1 
15.6 
53.5 
76.9 
93.6 
100.0 
37.degree. C./80% RH 
12.42 262.6 
2.1 
6.1 
12.6 
35.1 
56.2 
75.1 
86.1 
1 mo. 
__________________________________________________________________________ 
The above results demonstrate that there was a slowing of the dissolution 
of hydromorphone HCl from the coated beads when the beads were subjected 
to accelerated storage conditions. 
EXAMPLE 3 
Protecting the Retardant Coating 
In order to determine if the slowing of the dissolution of the 
hydromorphone beads of Example 2 was due to a stability problem between 
the hydromorphone and the retardant, in Example 3 Nu pariel hydromorphone 
beads were prepared according to Example 1, then overcoated with 5% HPMC, 
and tested without the retardant layer. Dissolution tests were conducted 
initially, and after storage at accelerated conditions of 37.degree. C. 
dry and 37.degree. C./80%RH. 
The results of the dissolution tests for Example 3 are set forth in Table 4 
below: 
TABLE 4 
______________________________________ 
Hydromorphone HCl 8 mg Controlled Release Capsules 
Stability Data Summary 
Hydro- Average 
morphone Weight 
Testing Time 
HCl (mg) 1 hr 2 hr 
______________________________________ 
Initial 8.49 166 100.0 
100.0 
37.degree. C. dry 
1 month 8.49 167 100.0 
100.0 
2 months 8.49 167 100.0 
100.0 
37.degree. C./80% RH 
1 month 8.49 167 100.0 
100.0 
2 months 8.49 170.3 100.0 
100.0 
______________________________________ 
The results of Example 3 show that the coated beads which did not include a 
retardant coating were stable. 
In order to determine the relative humidity under "dry conditions" in the 
oven, the relative humidity in a water-filled desiccator in a 60.degree. 
C. oven was determined as follows. First, about 500 grams of purified 
water is poured into a plastic desiccator and the metal guard inserted. A 
hygrometer/temperature indicator is placed on top of the guard and the 
desiccator covered and placed in the 60.degree. C. oven for 24 hours. 
After 24 hours the relative humidity in the desiccator was 85% while the 
temperature was still 60.degree. C. On placing the hygrometer alone in the 
60.degree. C. oven for 24 hours, the relative humidity was 9% at 
60.degree. C. 
EXAMPLE 4 
Prior Art Curing (According to Literature Recommendations) 
In Example 4, hydromorphone beads prepared according to Example 3 were 
coated with the Eudragit.RTM. RS to a 5% weight gain. After application of 
the coating, the beads were dried (cured) at 45.degree. C. in a fluidized 
bed dryer for 2 hours. This temperature is above the Tg of Eudragit.RTM. 
RS 30D, plasticized with Triethylcitrate at 20% level of solids. 
Dissolution tests were conducted initially, and after storage at 
37.degree. C. dry and 37.degree. C./80%RH. The results are set forth in 
Table 5 below: 
TABLE 5 
__________________________________________________________________________ 
Hydromorphone HCl 8 mg Controlled Release Capsules 
Stability Data Summary 
Hydromor- 
Average 
Testing phone Weight 
Time HCl (mg) 1 hr 
2 hr 
4 hr 
8 hr 
12 hr 
18 hr 
__________________________________________________________________________ 
2 hours* 
8.50 178.5 
8.0 
21.8 
45.7 
79.3 
94.2 
37.degree. C. dry 
1 mo. 8.50 177 16.8 
25.8 
44.2 
67.8 
80.8 
2 mo. 8.39 174 24.6 
40.8 
61.8 
83.4 
94.0 
100.0 
37.degree. C./80% RH 
1 mo. 8.50 174 48.8 
60.1 
80.7 
94.0 
100.0 
2 mo. 8.55 178 53.6 
76.3 
90.7 
98.2 
100.0 
__________________________________________________________________________ 
*initial dissolution after curing 
From the results provided above, it can be seen that the hydromorphone 
dissolution from the beads underwent significant changes upon storage, and 
that the short curing step recommended in the literature and utilized in 
Example 4 did not to help the stability/curing problem. 
EXAMPLES 5-7 
Optimizing curing and Ingredients of Retardant Coating 
The results obtained from Examples 2-4 indicated that the dissolution of 
the beads overcoated with a retardant coating seemed to slow down to a 
point and no further. However, the endpoint dissolutions achieved were too 
slow. 
In Examples 5-7, additional tests were conducted to determine processing 
conditions required during manufacture to cure the product to its endpoint 
dissolution. 
In order to obtain a formulation having a more suitable dissolution curve, 
and, rather than reduce the coating to less than 5% weight gain, the more 
soluble Eudragit.RTM. RL (methacrylic ester 1:20 quaternary ammonium 
groups) was included in the retardant coat. 
In Examples 5-7, the hydromorphone beads prepared pursuant to Example 4, 
except that they were overcoated with a 5% HPMC to protect the retardant 
coating from the environment. In Example 5, the retardant coating 
consisted of 100% Eudragit.RTM. RL. In Example 6, the retardant coating 
consisted of 50% Eudragit.RTM. RL and 50% Eudragit.RTM. RS. Finally, In 
Example 7, the retardant coating consisted of 10% Eudragit.RTM. RL: 
Eudragit.RTM. 90% RS. Each of Examples 5-7 were coated to total weight 
gain of 5%. 
Each of the HPMC-protected coatings of Examples 5-7 were cured to 1, 2, 7, 
10, 21 and 30 days at 45.degree. C. dry, at which times dissolution 
studies as set forth in Example 2 were conducted. 
Only Example 7 showed a desirable release profile, and curing was complete 
after only one day. Dissolution studies of the products of Examples 5 and 
6 showed the same to be immediate release products, the amount/type of 
retardant used not being sufficient to prevent immediate release of the 
drug (i.e., about 100% of the drug being released after one hour), even 
after the formulations were cured. Example 7 was further tested by storing 
under accelerated conditions as follows. After curing for 21 days, the 
samples of Example 7 were placed in a 37.degree. C./80%RH oven, and 
dissolution tests as set forth in Example 2 were conducted after 7 and 30 
days. Representative dissolution profiles for Example 7 (mean results for 
three samples) are set forth in Table 6 below: 
TABLE 6 
__________________________________________________________________________ 
Hydromorphone HCl 8 mg ND CR Eudragit .RTM. 5% Beads 
Curing Percent Hydromorphone HCl Dissolved 
Time Wt (mg) 
1 hr 
2 hr 
4 hr 8 hr 
12 hr 
18 hr 
24 hr 
__________________________________________________________________________ 
Initial 191 16.6 
53.1 
69.3 86.7 
95.6 
99.3 
100.0 
Mean 
1 day 190.7 
7.1 33.1 
66.6 87.3 
99.5 
97.9 
99.0 
Mean 
2 days 190.7 
7.4 35.0 
67.0 87.4 
95.1 
98.4 
99.2 
Mean 
7 days 190.7 
8.0 36.3 
67.7 86.6 
93.3 
96.8 
98.4 
Mean 
10 days 191.3 
7.2 36.5 
68.9 88.5 
94.8 
98.0 
99.5 
Mean 
21 days 191 6.9 36.1 
66.9 86.2 
92.7 
99.8 
99.0 
Mean 
30 days 190.3 
5.83 
31.9 
65.2 82.7 
90.4 
96.3 
96.7 
Mean 
Storage Time/Conditions 
30.degree. C./80% RH 
7 days 190.7 
5.9 25.1 
62.7 84.6 
92.6 
97.6 
99.5 
Mean 
30 days 190.3 
5.8 31.9 
65.2 82.7 
90.4 
96.3 
96.9 
Mean 
__________________________________________________________________________ 
The results set forth in Table 6 demonstrate that the 1 month dissolution 
profile showed no slowdown as compared to the initial cured sample, even 
for the samples tested under accelerated conditions. Thus, after curing 
for 24 hours at 45.degree. C., the methacrylate controlled release film 
coating was essentially stabilized. 
EXAMPLES 8-10 
Optimizing Retardant Coating Thickness 
In Examples 8-10, additional experimentation was conducted to determine the 
optimum weight of methacrylate polymer to use for a desirable release 
profile and to determine reproducibility and effectiveness of the 48 hour 
curing step at 45.degree. C. dry. Three batches were manufactured at 
different levels of methacrylate load and cured in a 45.degree. C. dry 
oven. 
In Example 8, hydromorphone beads were prepared in accordance with those of 
Example 3, as set forth in Table 7 below: 
TABLE 7 
______________________________________ 
Hydromorphone HCl MD Beads 
Ingredients Percent (by wt) 
Amt/Unit (mg) 
______________________________________ 
Hydromorphone HCl 
4.75% 4 
Nupariels Pa 18/20 
87.89% 74 
Opadry Lt Pink Y-5-1442 
2.38% 2 
Opadry Lt Pink Y-5-1442 
4.99% 4.2 
100% 84.2 
______________________________________ 
The hydromorphone beads were then further processed in accordance with 
Example 5. In Example 7, the retardant coating was Eudragit.RTM. RS, 
Eudragit.RTM. RL 90:10 (5% w/w coating). The formula for Example 7 is set 
forth in Table 8 below: 
TABLE 8 
______________________________________ 
Hydromorphone HCl MD CR Eudragit .RTM. 5% Beads 
Ingredients Percent (by wt) 
Amt/Unit (mg) 
______________________________________ 
Hydromorphone beads 
87.96% 84.2 mg 
Eudragit .RTM. RS 30D (90%) 
3.97% 3.8 mg 
Eudragit .RTM. RL 30D (10%) 
0.42% 0.4 mg 
TEC (20% of RS & RL) 
0.88% 0.84 mg 
Talc (40% of RS & RL) 
1.75% 1.68 mg 
Purified water qs 
Opadry Lt Pink Y-5-1442 
5.01% 4.8 
100% 95.72 mg 
______________________________________ 
Examples 9 and 10 are prepared in similar fashion to Example 7. In Example 
9, the retardant coating was Eudragit.RTM. RS, Eudragit.RTM. RL 90:10 (8% 
w/w coating). In Example 10, the retardant coating was Eudragit.RTM. RS, 
Eudragit.RTM. RL 90:10 (12% w/w coating). The formulas for Examples 9 and 
10 are set forth in Tables 9 and 10, respectively, below: 
TABLE 9 
______________________________________ 
Hydromorphone HCl MD CR Eudragit .RTM. 8% Spheres 
Ingredients Percent (by wt) 
Amt/Unit (mg) 
______________________________________ 
Hydromorphone beads 
84.2% 84.2 
Eudragit .RTM. RS 30D (90%) 
6.07% 6.07 
Eudragit .RTM. RL 30D (10%) 
0.67% 0.67 
TEC (20% of RS & RL) 
1.35% 1.35 
Talc (40% of RS & RL) 
2.70% 2.70 
Purified water qs 
Opadry Lt Pink Y-5-1442 
5.0% 5.0 
99.99% 99.99 
______________________________________ 
TABLE 10 
______________________________________ 
Hydromorphone HCl MD CR Eudragit .RTM. 12% Spheres 
Ingredients Percent (by wt) 
Amt/Unit (mg) 
______________________________________ 
Hydromorphone beads 
79.69% 84.2 
Eudragit .RTM. RS 30D (90%) 
8.61% 9.1 
Eudragit .RTM. RL 30D (10%) 
0.95% 1.0 
TEC (20% of RS & RL) 
1.91% 2.02 
Talc (40% of RS & RL) 
3.82% 4.04 
Purified water qs 
Opadry Lt Pink Y-5-1442 
5.02% 5.3 
100% 105.66 
______________________________________ 
Each of Examples 9-10 were cured on paper lined trays in a 45.degree. C. 
oven for two days after the application of the Eudragit.RTM. Controlled 
Release Coating and the HPMC 5% overcoating. Dissolution studies were then 
conducted on Examples 8-10. 
Initial dissolution profiles (after curing) of Example 8 showed it to 
resemble Example 7 (the products of both Examples were overcoated with a 
5% w/w Eudragit.RTM. coating). After curing for 2 days, samples of Example 
8 were subjected to further tests at room temperature, and under 
accelerated conditions of 37.degree. C./80%RH, 37.degree. C. dry and 
50.degree. C. dry. Representative dissolution profiles for Example 8 (mean 
results for three samples) are set forth in Table 11 below: 
TABLE 11 
__________________________________________________________________________ 
Hydromorphone HCl CR 8 mg Eudrgit .RTM. 5% Capsules 
Percent Hydromorphone HCl Dissolved 
Time Wt (mg) 
1 hr 
2 hr 
4 hr 
8 hr 
12 hr 
18 hr 
24 hr 
__________________________________________________________________________ 
2 days* 191.3 
6.3 36.2 
69.3 
87.8 
97.3 
100.0 
Mean 
RT 191.1 
6.0 30.8 
63.1 
83.4 
91.8 
96.3 
97.9 
1 mo. 
Mean 
37.degree. C./80% RH 
1 mo. 191.6 
6.9 28.5 
63.2 
84.5 
91.5 
95.6 
97.8 
Mean 
2 mo. 194.3 
11.4 
35.6 
70.7 
90.5 
96.8 
100 
Mean 
37.degree. C. Dry 
192.0 
11.4 
35.1 
68.6 
87.9 
94.5 
98.9 
100 
1 mo. 
Mean 
50.degree. C. Dry 
191.4 
11.1 
41.4 
70.6 
90.4 
96.5 
100 
1 mo. 
Mean 
Comparison to Example 9 (1 day and 2 day dissolutions) 
1 day 190.7 
7.1 33.1 
66.6 
87.3 
99.5 
97.9 
99.0 
Mean 
2 Days 190.7 
7.4 35.0 
67.0 
87.4 
95.1 
98.4 
99.2 
Mean 
__________________________________________________________________________ 
*initial dissolution after curing 
As can be seen from the dissolution results provided for Example 8, 
although the dissolution profile of the samples were not taken after 1 day 
of curing, the results obtained after 2 day curing are substantially 
similar to the results obtained for the 1 and 2 day curings of Example 7. 
Therefore, it is hypothesized that the product of Example 8 was also 
stable after one day curing. 
After curing for 2 days, samples of Example 9 were tested for dissolution, 
and then samples of Example 9 were exposed to accelerated conditions of 
37.degree. C./80%RH for one month. Representative initial dissolution 
profiles (mean results for three samples) for Example 9 are set forth in 
Table 12 below: 
TABLE 12 
__________________________________________________________________________ 
Hydromorphone HCl CR 8 mg Eudragit .RTM. 8% Capsules 
Percent Hydromorphone HCl Dissolved 
Time Wt (mg) 
1 hr 
2 hr 
4 hr 
8 hr 
12 hr 
18 hr 
24 hr 
__________________________________________________________________________ 
2 days* 201.3 
0.8 3.3 
40.0 
78.4 
90.7 
97.5 
99.9 
Mean 
37.degree. C./80% RH 
7.3 8.6 
34.1 
72.8 
85.5 
93.2 
97.2 
1 mo. 
Mean 
__________________________________________________________________________ 
*initial dissolution after curing 
As can be seen from the dissolution results provided above for Example 9, 
the results obtained after 2 day curing are substantially similar to the 
results obtained under accelerated storage conditions of 37.degree. 
C./80%RH, thus indicating the stability of Example 9 after a 2 day curing. 
Furthermore, the dissolution results obtained with Example 9 showed slower 
release rates of hydromorphone, as would be expected given the thicker 
retardant coating. 
After curing for 2 days, samples of Example 10 were tested for dissolution, 
and then samples of Example 10 were subjected to further tests after 
storing for one month at room temperature, and under accelerated 
conditions of 37.degree. C./80%RH, 37.degree. C. dry and 50.degree. C. 
dry. Representative dissolution profiles (mean results for three samples) 
for Example 10 are set forth in Table 13 below: 
TABLE 13 
__________________________________________________________________________ 
Hydromorphone HCl CR 8 mg Eudragit .RTM. 12% Capsules 
Percent Hydromorphone HCl Dissolved 
Time Wt (mg) 
1 hr 
2 hr 
4 hr 
8 hr 
12 hr 
18 hr 
24 hr 
__________________________________________________________________________ 
2 days* 215.3 
0.8 3.1 
9.3 70.9 
90.4 
100.8 
104.8 
Mean 
RT 210.8 
0 1.8 
4.6 62.9 
84.3 
96.1 
99.8 
1 mo. 
Mean 
37.degree. C./80% RH 
213.8 
2.2 4.8 
7.2 50.8 
74.3 
87.3 
93.3 
1 mo. 
Mean 
37.degree. C. Dry 
210.4 
0.8 2.2 
6.9 59.7 
82.2 
96.3 
100 
1 mo. 
Mean 
50.degree. C. Dry 
207.3 
1.6 1.5 
3.3 51.5 
76.2 
90.9 
97.4 
1 mo. 
Mean 
__________________________________________________________________________ 
*initial dissolution after curing 
As can be seen from the dissolution results provided above for Example 10, 
the dissolution results obtained with Example 10 showed slower release 
rates of hydromorphone as compared to the thinner retardant coatings of 
Examples 8 and 9, as expected. The overall results obtained after 2 day 
curing are substantially similar to the results obtained under accelerated 
storage conditions of 37.degree. C./80%RH, with the exception of the 
percent drug dissolved at the 8 hour and 12 hour points. These results 
might indicate that at high loads of retardant coating, it may be 
necessary to cure the coating for a longer period of time to attain a 
stabilized formulation. 
EXAMPLE 11 
Morphine Sulfate Coated Beads 
In Example 11, the curing step of the present invention was applied to a 
formulation in which morphine sulfate was substituted as the drug. 
A suspension of morphine sulfate and HPMC (Opadry.RTM. Clear Y5-7095) was 
applied onto 18/20 mesh nupariel beads in a fluid bed dryer with a Wurster 
insert at an inlet temperature of 60.degree. C. An Opadry.RTM. Lavender 
YS-1-4729 HPMC Base filmcoating suspension was then applied after drug 
loading as a protective coat at a 5% weight gain. 
After the overcoating process was completed, the morphine sulfate beads 
were then overcoated with a retardant coating mixture of Eudragit.RTM. RS 
30D and Eudragit.RTM. RL 30D at a ratio of 90:10, RS to RL, at a 5% weight 
gain level. The application of this mixture of Eudragit.RTM. RS 30D and 
Eudragit.RTM. RL 30D along with talc (included as an anti-tacking agent) 
and triethyl citrate (plasticizer) was done at an inlet temperature of 
35.degree. C. in a Wurster Insert. 
Once the retardant overcoating was complete, the morphine sulfate beads 
were given a final overcoating of Opardry.RTM. lavender YS-1-4729 at a 5% 
weight gain level. 
After completion of the final filmcoating process, the morphine sulfate 
beads were cured on paper lined trays in a 45.degree. C. dry oven for 2 
days. After curing, the beads were filled into gelatin capsules at a 30 mg 
morphine sulfate strength. The final formula is provided in Table 14 
below: 
TABLE 14 
______________________________________ 
Processing Step 
Ingredient Mg/Capsule 
______________________________________ 
Drug Load Morphine Sulfate 30 mg 
Nupariel PG 18/20 255 mg 
Opadry .RTM. Clear Y-5-7095 
15 mg 
First Overcoat 
Opadry .RTM. Lavender YS-1-4729 
15.8 mg 
Retardant Eudragit .RTM. RS 30D 
14.2 mg 
Overcoat Eudragit .RTM. RL 30D 
1.6 mg 
Triethylcitrate 3.2 mg 
Talc 6.3 mg 
Final Overcoat 
Opadry .RTM. Lavender YS-1-4729 
18.0 mg 
Total: 359.1 mg 
______________________________________ 
Dissolution stability studies were then conducted on the product of Example 
11 after the above-mentioned curing step at storage conditions of room 
temperature, 37.degree. C./80%RH, 37.degree. C. dry, and 50.degree. C. dry 
after one month and after two months. The results are set forth in Table 
15 below: 
TABLE 15 
__________________________________________________________________________ 
Morphine Sulfate CR 30 mg Eudragit .RTM. 5% Capsules 
Percent Morphine Sulfate Dissolved 
Time 1 hr 
2 hr 
4 hr 
6 hr 
8 hr 
12 hr 
18 hr 
24 hr 
__________________________________________________________________________ 
2 days* 0.0 43.5 
74.9 
-- 91.8 
95.3 
99.8 
100 
Mean 
RT 
1 mo. 0.0 36.9 
73.8 
86.9 
92.2 
96.5 
99.9 
100 
Mean 
2 mo. 2.0 37 72 82 88 92 96 99 
Mean 
37.degree. C./80% RH 
1 mo. 0.0 28.4 
70.3 
84.8 
92.1 
97.7 
100 
Mean 
2 mo. 1.9 30.1 
68.4 
79.9 
87.0 
93.5 
95.6 
97.8 
Mean 
37.degree. C. Dry 
1 mo. 0.0 32.0 
72.5 
86.0 
93.2 
97.3 
100 
Mean 
2 mo. 0.9 26.4 
67.5 
78.8 
88.6 
94.0 
98.0 
99.5 
Mean 
50.degree. C. Dry 
1 mo. 0.0 37.7 
74.1 
89.3 
93.7 
98.5 
100 
Mean 
2 mo. 2.0 33.0 
74 85 94 98 100 
Mean 
__________________________________________________________________________ 
*initial dissolution after curing 
The results set forth in Table 15 demonstrate that the curing process 
stabilized the dissolution profile of the morphine sulfate to an endpoint 
dissolution rate which substantially remained constant, even for the 
samples stored under accelerated conditions. 
EXAMPLE 12 
Controlled Release Hydromorphone HCl 8 mg Formulations--Acrylic Polymer 
Coating 
Example 12 is prepared as follows: 
1. Drug Loading. Hydromorphone beads were prepared by dissolving 
hydromorphone HCl in water, adding Opadry Y-5-1442, light pink (a product 
commercially available from Colorcon, West Point, Pa., which contains 
hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, 
polyethylene glycol and D&C Red No. 30 aluminum lake) and mixing for about 
1 hour to obtain a 20% w/w suspension. This suspension was then sprayed 
onto Nu-Pareil 18/20 mesh beads using a Wurster insert. 
2. First Overcoat. The loaded hydromorphone beads were then overcoated with 
a 5% w/w gain of Opadry Light Pink using a Wurster insert. This overcoat 
was applied as a protective coating. 
3. Retardant Coat. After the first overcoat, the hydromorphone beads were 
then coated with a 5% weight gain of a retardant coating mixture of 
Eudragit RS 30D and Eudragit RL 30D at a ratio of 90:10, RS to RL. The 
addition of Triethyl Citrate (a plasticizer) and Talc (anti-tacking agent) 
was also included in the Eudragit suspension. The Wurster insert was used 
to apply the coating suspension. 
4. Second Overcoat. Once the retardant coating was complete, the 
hydromorphone beads were given a final overcoat of Opadry Light Pink to a 
5% weight gain using a Wurster insert. This overcoat was also applied as a 
protective coating. 
5. Curing. After the completion of the final overcoat, the hydromorphone 
beads were cured in a 45.degree. C. oven for 2 days. The cured beads were 
then filled into gelatin capsules at an 8 mg Hydromorphone strength. The 
complete formula for the beads of Example 12 is set forth in Table 16 
below: 
TABLE 16 
______________________________________ 
Processing Step 
Ingredient % mg/unit 
______________________________________ 
Drug Loading Hydromorphone 8.2 8.0 
HCl 
Nu-pariel 18/20 
73.3 74.0 
Opadry Lt Pink 
2.1 2.0 
First Overcoat 
Opadry Light Pink 
4.4 4.2 
Retardant Coat 
Eudragit RS 30D 
4.0. 3.8 
(dry wt.) 
Eudragit RL 30D 
0.4 0.4 
(dry wt.) 
Triethyl Citrate 
0.8 0.8 
Talc 1.8 1.7 
Second Overcoat 
Opadry Light Pink 
5.0 4.8 
Total: 100.0 99.7 mg 
______________________________________ 
Dissolution studies were conducted on the Eudragit-coated hydromorphone 
beads of Example 12 both initially and after 28 days. The results are set 
forth in Table 17 below: 
TABLE 17 
______________________________________ 
Time 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 
24 hr 
______________________________________ 
Initial 17.2 48.4 77.4 93.3 97.2 98.8 98.8 
28 days 16.8 50.6 79.7 95.2 99.0 101.9 
102.7 
at 37.degree. C./ 
80% RH 
______________________________________ 
The stability studies of the Eudragit-coated hydromorphone beads as set 
forth in Table 17 below show the initial dissolution to be the same as the 
dissolution done on samples placed at a 37.degree. C./80% RH condition. 
EXAMPLE 13 
In Example 13, a single dose six-way randomized cross-over study (one week 
wash-out) was conducted in 12 patients and compared to the results 
obtained with an equivalent dose of an immediate release preparation. 
Blood samples were taken initially, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 
3.5, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 48 hours after administration in 
order to determine plasma levels. Comparative Example 13A is 8 mg of a 
hydromorphone immediate release formulation (two tablets of Dilaudid.RTM. 
4 mg tablets, commercially available from Knoll). Example 13 is an 8 mg 
dose of the encapsulated hydromorphone beads of Example 12. 
The results obtained for Comparative Example 13A are set forth in FIG. 1. 
The results obtained for Example 5 are set forth in FIG. 2. FIG. 3 shows 
the plasma levels of Example 13 plotted against the results for 
Comparative Example 13A. The results for Example 13 are further set forth 
in Table 18 below, which provides data regarding area under the curve 
(bioavailability), the peak plasma concentration (C.sub.max), and the time 
to reach peak plasma concentration (T.sub.max). 
TABLE 18 
______________________________________ 
Product AUC Cmax Tmax PW@HH 
______________________________________ 
Example 13A 
2 Dilaudid 4 mg 
12427 .+-. 
3013 .+-. 1.10 .+-. 
1.67 .+-. 
Tablets 1792 539 0.14 0.22 
Example 13 
13707 .+-. 
1211 .+-. 4.42 .+-. 
7.79 .+-. 
1381 153 0.38 1.96 
Example 13 
110% 40% 402% 46% 
______________________________________ 
The results obtained for Example 13 showed that at the 12th hour after 
administration, the blood levels of hydromorphone are over 500 pg/ml 
hydromorphone, and at the 24th hour after administration, the plasma 
levels are well over 300 pg/ml. Therefore, this product is considered to 
be suitable for once a day administration. 
EXAMPLES 14-15 
In Examples 14-15, a single dose 4-way randomized cross-over study was 
conducted in 10 subjects. Example 14 was an 8 mg dose of the hydromorphone 
beads of Example 13--fasted; whereas Example 15 is an 8 mg dose of the 
hydromorphone beads of Example 13--fed. In Comparative Example 14A, 8 mg 
of immediate release hydromorphone (2 Dilaudid 4 mg tablets) were 
administered--fasted. In Comparative Example 15A, 8 mg of immediate 
release hydromorphone (2 Dilaudid 4 mg tablets) were administered--fed. 
The plasma levels for Comparative Examples 14A and 15A are set forth in 
FIG. 4, whereas the plasma levels for Examples 14 and 15 are set forth in 
FIG. 5. The results for Examples 16-17 and Comparative Examples 16A and 
17A are further set forth in Table 21, which provides data regarding area 
under the curve and percent absorbed as compared to immediate release 
(bioavailability), the peak plasma concentration (C.sub.max), and the time 
to reach peak plasma concentration (T.sub.max). 
TABLE 19 
______________________________________ 
Group AUC % IR T.sub.max 
C.sub.max 
______________________________________ 
Example 14 21059 101 4.9 1259 
Example 15 25833 106 4.6 1721 
Example 14A 20903 100 0.85 3816 
Example 15A 24460 100 1.15 3766 
______________________________________ 
As can be ascertained from the results provided by Examples 14-15 and 
Comparative Examples 14A and 15A, there is a minimal food effect for both 
the immediate release tablets and the controlled-release beads of Examples 
14 and 15, with a small increase in bioavailability for the 
controlled-release beads of Examples 14 and 15. The plasma levels again 
confirm that this product is suitable for once a day administration. In 
the 24th hour, the controlled-release product provides plasma levels of 
nearly 600 pg/ml and at the 12th hour provided plasma levels of over 700 
pg/ml. 
EXAMPLES 16-17 
In Examples 16-17, a steady-state 3-way cross-over study is conducted for 4 
days. In Comparative Example 16A, the subjects are dosed with 8 mg 
immediate release hydromorphone (2 Dilaudid 4 mg tablets) every 6 hours. 
In Example 16, 8 mg of the hydromorphone beads of Example 15 are 
administered every 12 hours. In Example 17, 8 mg of the hydromorphone 
beads of Example 13 are administered every 24 hours. Blood samples are 
taken on the fourth day. 
The plasma levels for Comparative Example 16A versus the plasma levels for 
Examples 16 and 17 are set forth in FIG. 6. The trough levels for 
Comparative Example 16A versus the levels for Examples 16 and 17 are set 
forth in FIG. 7 (the values for Example 17 are doubled in FIG. 7). The 
results for Examples 16-17 and Comparative Example 16A are further set 
forth in Table 20, which provides data regarding area under the curve and 
percent absorbed as compared to immediate release (bioavailability), the 
peak plasma concentration (C.sub.max), and the time to reach peak plasma 
concentration (T.sub.max). 
TABLE 20 
______________________________________ 
Group AUC AUC* T.sub.max 
C.sub.max 
C.sub.max * 
______________________________________ 
Example 16 
62223 27595 5.5 3475 2232 
Example 17 
39233 28879 4.8 2730 2189 
Comparative 
47835 22236 1.0 3124 2163 
Example 16A 
______________________________________ 
*AUC = 0-12 hr. for Q12H, 0-24 hr. for Q42H, and 0-12 hr. for Q6H 
*C.sub.max = C.sub.max minus zero time value 
With reference to the area under the curve (AUC) as a measure of 
bioavailability, it can be ascertained from the data provided in Table 20 
that Comparative Example 16A and Examples 16 and 19 all have an equivalent 
AUC increased over the dosing interval, indicating that all dosage regimes 
are bioavailable. 
Furthermore, in this study, Example 17, which was only dosed at 8 mg every 
24 hours, shows that this formulation provides an excellent 24 hour 
preparation if the amount of beads are doubled to provide a once a day 
dosage of 16 mg, which is the equivalent amount of hydromorphone dosed by 
the immediate release formulation (4 mg every 6 hours). The minimum or 
trough concentration shown in FIG. 9 for Example 17 show that this product 
will be the equivalent of the 4 mg immediate release formulation (dosed 
every 6 hours), and therefore this would provide an excellent once a day 
product. 
EXAMPLE 18 
Controlled-Release Morphine Sulfate 30 mg Formulation--Acrylic Polymer 
Coating 
Example 18 is prepared in the same manner as the above Examples. The 
complete formula for the beads of Example 18 is set forth in Table 21 
below: 
TABLE 21 
______________________________________ 
Ingredients Amt/Unit 
______________________________________ 
Drug Loading 
Morphine Sulfate Powder 
30.0 mg 
Lactose Hydrous Impalpable 
42.5 mg 
Povidone 2.5 mg 
Nupareil PG 18/20 125.0 mg 
Purified Water qs 
Opadry Red YS-1-1841 10.5 mg 
Purified Water qs 
Retardant Coating 
Eudragit RS30D 10.3 mg 
Eudragit RL30D 0.2 mg 
Triethyl Citrate 2.1 mg 
Talc 4.2 mg 
Purified Water qs 
Second Overcoat 
Opadry Red YS-1-1841 12.0 
Purified Water qs 
Total 239.3 mg 
______________________________________ 
The ratio of Eudragit.RTM. RS 30D to Eudragit.RTM. RL30D is 98:2. After 
completion of the final overcoat, the morphine beads are cured in a 
45.degree. C. oven for 2 days. The cured beads are then filled into 
gelatin capsules at a 30 mg strength. 
The finished product is subjected to dissolution testing initially; after 
being stored for 3 months and 6 months at room temperature; and after 
exposure to accelerated storage conditions (40.degree. C./75% RH) for one 
month, two months and three months. The results are set forth in Table 22 
below: 
TABLE 22 
______________________________________ 
Storage Dissolution (% Dissolved) Time (Hr) 
Conditions 1 2 4 8 12 
Testing Time 
Hr. Hrs. Hrs. Hrs. Hrs. 
______________________________________ 
Initial 2.6 24.7 60.5 89.4 98.8 
1 Month 5.8 27.3 62.0 89.8 99.1 
40.degree. C./ 
75% RH 
3 Months 6.8 26.5 65.3 87.6 95.1 
40.degree. C./ 
75% RH 
3 Months RT 
6.4 24.4 56.8 83.5 93.2 
6 Months RT 
5.6 21.1 55.0 84.2 94.8 
______________________________________ 
The dissolutions set forth in Table 22 show the beads of Example 18 to be 
stable. 
A double-blind single dose cross-over study is then conducted in 12 
subjects with regard to the dosage form of Example 18 against a standard, 
commercially available controlled-release morphine sulfate tablet 
(Comparative Example 18A; MS Contin.RTM. 30 mg tablets, available from the 
Purdue Frederick Company). The results are set forth in Table 23. 
TABLE 23 
______________________________________ 
Example 18 
Pharmacokinetic 
MS Contin 5% Eudragit Coating 
Parameter (Fasted) (RS:RL, 98:2) (Fasted) 
______________________________________ 
AUC 76.2 93.6 
T.sub.max 2.2 6.1 
C.sub.max 9.4 6.2 
______________________________________ 
From the data obtained from Example 18, it appears that the product may be 
suitable for once-a-day administration. 
EXAMPLES 19-20 
Therefore, in Examples 19-20, high load base beads are produced which have 
a higher load of morphine sulfate so that larger doses can be easily 
administered once-a-day. The high load beads are prepared via powder 
layering in a Glatt Rotor Processor. The formulation for Example 19-20 is 
set forth in Table 23 below: 
TABLE 23 
______________________________________ 
High Load 
Ingredients Bead mg 
______________________________________ 
Morphine 30.0 
Sulfate 
Lactose 6.0 
Povidone C-30 1.25 
Sugar Beads 7.75 
Opadry 2.37 
Purified Water qs 
47.37 
______________________________________ 
Since the base beads are different in comparison to the low load beads used 
in Example 18, more of the relatively soluble Eudragit.RTM. RL is included 
in the formula, as well as an extra HPMC protective coat between the 
Eudragit.RTM. layer and the morphine immediate release layer to further 
enhance stability. 
The formula for the 60 mg dose is set forth in Table 24: 
TABLE 24 
______________________________________ 
Ingredient Amt/60 mg Unit (mg) 
______________________________________ 
Morphine (high load) base beads 
85.26 
Retardant Coating 
Eudragit RS 30D 4.2 
Eudragit RL 30D 0.1 
Triethyl Citrate 0.9 
Talc 1.7 
Overcoatings 
Opadry Blue YS-1-10542A 
4.9 
Purified Water qs 
Morphine Sulfate Powder 
6.0 
Opadry Blue YS-1-10542A 
5.10 
Purified Water qs 
108.16 
______________________________________ 
The beads are then cured in a 45.degree. C. oven for 2 days, and thereafter 
are divided into two portions. Portion 1 is filled into hard gelatin 
capsules at a strength equivalent to 60 mg and portion 2 is filled into 
hard gelatin capsules at a strength equivalent to 30 mg. 
Dissolution studies are conducted on both strength capsules. The data shows 
that the percent morphine dissolved is identical at both strengths. 
Stability studies are conducted with the 60 mg capsules. The results for 
the 60 mg capsules is set forth in Table 25 below: 
TABLE 25 
______________________________________ 
Storage Dissolution (% Dissolved) Time (Hr) 
Conditions 1 2 4 8 12 14 
Time Hr. Hrs. Hrs. Hrs. Hrs. Hrs. 
______________________________________ 
Initial 11.0 14.0 24.0 44.1 58.9 83.3 
1 Month 11.9 14.9 25.0 43.6 56.6 85.1 
40.degree. C./75% RH 
2 Months 11.7 14.7 25.7 48.5 65.5 93.1 
40.degree. C./75% RH 
______________________________________ 
A bioavailability study is then conducted using the 30 mg strength capsule 
(Example 19=fasted; Example 20=fed) with MS Contin 30 mg--fasted (Example 
19A) as a reference. 
The results are set forth in Table 26. 
TABLE 26 
______________________________________ 
Example 19 Example 20 
Pharmaco- High Load High Load 
kinetic MS Contin with 10% IR with 10% IR 
Parameter 
(Fasted) Overcoat (Fasted) 
Overcoat (Fed) 
______________________________________ 
AUC 114 141 118 
T.sub.max 
2.8 12.9 8.0 
C.sub.max 
11.6 4.0 5.4 
______________________________________ 
FIG. 8 is a graph showing the plasma levels of Examples 19-20 (both fed and 
fasted) versus the plasma levels obtained with Comparative Example 19A. 
From the data obtained, it appears that the product is suitable for 
once-a-day administration. 
EXAMPLE 21 
Controlled Release Acetaminophen (APAP) tablets are prepared in accordance 
with the present invention as follows: 
First, immediate release APAP cores are prepared by compressing Compap 
coarse L into tablet cores weighing 555.6 mg. Compap coarse L contains 
approximately 90% APAP along with pharmaceutical grade excipients 
including a binder, disintegrant and lubricant, and is a directly 
compressible material commercially available from Mallinckrodt, Inc., St. 
Louis, Mo. The APAP tablet cores include approximately 500 mg of APAP. The 
Compap coarse L is compressed using a rotary tablet press equipped with a 
7/16" round, standard concave cup, plain, tooling. The cores were 
compressed at a theoretical weight of 555.6 mg and at a hardness of about 
8-9 Kp. 
Next, the APAP tablet cores prepared above are coated with the controlled 
release coating of the present invention as follows: 
Appropriate amounts of Eudragit RS-30D and Eudragit RL-30D are combined, 
and purified water is added. The amount of purified water is calculated 
such that the final coating suspension will have a concentration of about 
20% of solids polymer, plasticizer and talc. Then triethyl citrate is 
added with mixing for 15 minutes. Thereafter, talc is added with mixing 
for an additional 15 minutes. The appropriate quantity of APAP tablet 
cores are loaded into an Accela Cota coating pan. The coating suspension 
is sprayed from an appropriate spray gun until a weight gain of 4% per 
tablet of the polymer coating is attained. 
After the spraying of the functional coat is completed, the tablets are 
sprayed with a film coat of Opadry. This coat is sprayed in a similar 
manner to the functional coat. 
Further information concerning the Controlled Coated APAP tablets is set 
forth in Table 27 below: 
TABLE 27 
______________________________________ 
Ingredients mg/tab 
______________________________________ 
APAP IR tablet cores 
555.60 
Eudragit RS-30D (solids) 
5.56 
Eudragit RL-30D (solids) 
16.66 
Triethyl citrate 4.44 
Talc 8.89 
Opadry White Y-5-7068 
18.28 
Purified Water qs 
Total 609.43 
______________________________________ 
After completion of the coating process, the functional coated tablets are 
discharged into a curing tray and cured in a chamber at a temperature of 
45.degree. C. for 48 hours. The results of dissolution testing for the 
coated tablets are set forth in Table 28 below: 
TABLE 28 
______________________________________ 
Test Period (Hours) 
% APAP Dissolved 
______________________________________ 
1 2.1 
2 4.8 
4 10.4 
8 20.0 
12 29.2 
18 41.2 
24 52.1 
______________________________________ 
EXAMPLE 22 
In Example 22, controlled release Acetaminophen (APAP)tablets are prepared. 
To provide a faster dissolution is required, the amount of Eudragit RL-30D 
is increased and the amount of Eudragit RS-30D is decreased. Consequently, 
controlled release APAP tablets are prepared containing only Eudragit 
RL-30D and no Eudragit RS-30D. APAP cores are made as described in Example 
4. Next, the APAP tablet cores prepared above are coated with the 
controlled release coating of the present invention as follows: Purified 
water is added to the Eudragit RL-30D. The amount of purified water is 
calculated such that the final coating suspension will have a 
concentration of about 20% of solids polymer, plasticizer and talc. Then, 
triethyl citrate is added with mixing for 15 minutes. Then, talc is added 
with mixing for an additional 15 minutes. The appropriate quantity of APAP 
tablet cores are loaded into an Accela Cota coating pan. The coating 
suspension is sprayed from an appropriate spray gun until a weight gain of 
4% per tablet of the polymers is attained. 
After the spraying of the functional coat is completed, the tablets are 
sprayed with a film coat of Opadry to prevent the tablets from sticking. 
This coat is sprayed in a similar manner to the functional coat. 
Further information concerning the Controlled Release Coated APAP tablets 
is set forth in Table 29 below: 
TABLE 29 
______________________________________ 
Ingredients mg/tab 
______________________________________ 
APAP IR tablet cores 
555.60 
Eudragit RL-30D (solids) 
22.22 
Triethyl citrate 4.44 
Talc 8.89 
Opadry White Y-5-7068 
18.28 
Purified Water qs 
Total 609.43 
______________________________________ 
After completion of the coating process, the functional coated tablets are 
discharged into a curing tray and cured in a chamber at a temperature of 
45.degree. C. for 48 hours. Dissolution testing of the coated tablets 
provides the data set forth in Table 30 below: 
TABLE 30 
______________________________________ 
Test Period (Hours) 
% APAP Dissolved 
______________________________________ 
1 2.5 
2 6.2 
4 14.6 
8 29.8 
12 42.0 
18 56.6 
24 68.1 
______________________________________ 
The examples provided above are not meant to be exclusive. Many other 
variations of the present invention would be obvious to those skilled in 
the art, and are contemplated to be within the scope of the appended 
claims.