Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Controlled Release Liquid Dosage Formulations
For Pharmaceuticals
Background of the Invention
1. Field of the Invention
- 05 This invention relates to controlled release
pharmaceuticals, specifically dual-coated controlled no-
lease pharmaceuticals as a liquid dosage formulation
which have substantial shelf life. More particularly,
this invention relates to and discloses liquid suspense
10 ions of dual coated controlled release dosage forms that
retain their controlled release characteristics even
though dispersed in a liquid medium for a significant
period of time prior to use.
2. Description of the Prior Art
Controlled release forms of medication are well
known in the art. Some such medications are prepared as
tablets in the form of a therapeutically active core
coated with various thicknesses of ingestible materials.
Other time release medications take the form of an in-
20 nocuous core coated with alternating layers of there-
poetical active materials and inactive ingestible ma-
trials. More recently micro capsules or micro spheres,
with selected proportions of the micro capsules having
coatings of differing solubilities) have been placed in
25 conventional gelatin capsules to yield controlled release
dosage forms.
Almost all controlled release pharmaceuticals
to date are solid sin the form of tablets, capsules, matrix
materials, micro capsules, reservoir-type tablets and mix
30 crucifiers. Such forms of delivery are not always ad van-
; tageous such as for administering time release drugs to
very young children or to very old individuals having
difficulty swallowing. An easily prepared and versatile
..
~393~7
-- 2 --liquid controlled release dosage formulation for delivery
of a pharmaceutical, especially one which could be pro-
packaged, would be a significant advancement.
US. Patent 2,805,977 (Robinson) discloses a
05 liquid dosage enteric preparation, however, the Robinson
formulation does not teach of any formulation having any
shelf life prior to administration. Robinson also does
not disclose the use of the dual coating of the present in-
mention so as to yield a liquid suspension of controlled
10 release dosage forms that retains its controlled release
characteristics even though dispersed in a liquid medium
for a significant period of time prior to use.
Definitions
"Dosage form" is defined as referring to the
15 solid carrier or housing vehicle for a therapeutically
active compound exhibiting controlled release. By way of
illustration, a dosage form would include any type of
common pill, and would also include, for example, tab-
lets, capsules, matrix materials, micro capsules, riser-
20 void type tablets, and micro spheres.
"Controlled release" is understood to mean no-
lease, preferably uniform release, of the active compound
over a span of time r thus would encompass such terms as
time-release, delayed release, and sustained release.
"Dosage formulation" is defined as referring to
the combination of dosage forms and liquid carrier in
which the dosage forms are dispersed.
summary of the Invention
It is an object of the present invention to
30 provide a liquid controlled release dosage formulation,
especially for pharmaceuticals.
It is an object of this invention to provide
such liquid controlled release dosage formulation having
3~7
-- 3 --
an extended and useful shelf life, generally in excess of
35 days.
It is an object of this invention to provide a
liquid suspension of dual-coated controlled release doss
05 age forms that retain their controlled release character-
is tics even though dispersed in a liquid medium for a
significant period of time prior to use.
It is a further object of this invention to
provide such dual-coated controlled release dosage forms
10 as an easily prepared and versatile liquid controlled
release dosage formulation.
The present invention relates to and discloses
compositions for making liquid suspensions of controlled
release dosage forms of therapeutically active compounds
15 that retain their controlled release characteristics even
though dispersed in a liquid medium for a significant
period of time prior to use.
The present invention can be applied to and sue-
cessfully used with any known solid controlled release
20 pharmaceutical to convert it into a liquid dosage forum-
lotion having significant shelf life while still no-
twining an acceptable controlled release profile upon
ingestion. The present invention can be applied to and
used with tablets, capsules, matrix materials, micro-
25 capsules, reservoir-type tablets, micro spheres and any
other type of controlled release dosage form capable of
being coated.
The present invention discloses use of a unique
combination dual coating of fats overreacted with eel-
30 lulls derivatives or prolamins and a liquid carrier for achieving a versatile liquid controlled release dosage
formulation having substantial shelf life prior to in-
gestion.
- -
Detailed Description of the Invention
The present invention is a controlled release
liquid dosage formulation for pharmaceuticals. The pros-
en invention discloses use of a unique combination of
ox dual coatings of controlled release type dosage forms in
combination with a suitable liquid carrier. Suitable con-
trolled release type dosage forms useful in the practice
of the present invention include tablets, capsules, con-
trolled-release matrix beads, micro capsules, reservoir-
10 type tablets, and micro spheres, all by way of example andante limitation.
In this invention, suitable controlled release
type dosage forms, preferably micro spheres, are coated
with at least two different materials. The first coating
15 is with a hydrophobic, digestible or degradable material
preferably having a melting point of approximately 120F
or lower such that the coating would be almost liquid or
rendered permeable following ingestion. The first coat-
in over said dosage forms can be a lipid including a fat,
20 a fatty acid, fatty alcohol, wax, ester or mixtures
thereof, having a melting point of less than 120F. The
first coating preferably is one or more fats, i.e.,
glycerides composed of fatty acids of from 3 to 22 carbons,
with said glycerides or blends of glycerides having a
25 melting point of 120F or less. It is to be understood by
those skilled in the art that most fats or glycerides
include minor percentages of strolls, hydrocarbons, to-
copherols and other non glyceride constituents. The fats
or glycerides can include moo-, do-, or triglycerides or
30 glycerol esters, phosphatides, phosphoglycerides, or mix-
lures thereof. The first coating is, preferably, a hard
butter such as cocoa butter, or partially hydrogenated
cottonseed and/or soybean vegetable oil such as Camille
(Derek) which has a Wiley melting point of 97-101F. Also
35 useful for the first coatings are: animal fats, tallow;
shortening; lard including modified lard; vegetable oils
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9 3
including partially hydrogenated vegetable oils; beeswax;
lecithin; butterfat; oleic acid; elaidic acid; margarine;
or blends of any of the foregoing.
It is to be understood that melting point is an
05 approximate term when applied to fats, waxes, fatty acids
and esters since these materials melt over a range of
temperature.
Melt point determination techniques have been
established by the Fat Analysis Committee of the American
10 Oil Chemists' Society such as ARCS Method Cc 2-38 Wiley
Melting Point and ARCS Method Cc 3-25.
The first coating can be a fat, fatty acid,
fatty alcohol, wax, ester, or mixture thereof having a
melting point of less than approximately 120F or capable
15 of being rendered permeable following ingestion.
Substances useful as the first coating include
moo-, do-, and triglycerides composed of fatty acids of
from 3 to 32 carbons; wax esters composed of fatty acids
of from 3 to 36 carbons and composed of alcohols of from
20 8 to 46 carbons; fatty alcohols of from 8 to 54 carbons;
hydrocarbons of from 18 to 54 carbons: olefins of from 18
to 54 carbons, and free fatty acids of 8 to 36 carbons, all
additionally having a melting point below approximately
120F or capable of being rendered permeable following
25 ingestion.
The waxes making up the first coating can in-
elude, by way of illustration and not limitation:
wax hydrocarbons - such as n - alikeness and
branched alikeness, olefins, cyclic alikeness and isoprenoid
30 hydrocarbons; kittens such as monoketones, I- Dakotans,
wax alcohols - such as secondary alcohols and
Al Kane dills,
wax acids - such as alkanoic and alkenoic acids,
o- or I- hydroxy acids, and
wax esters - such as primary alcohol esters,
secondary alcohol esters, divester waxes, Al Kane dill dip
I 7
-- 6 --esters, divesters of hydroxy acids, trimesters, trimly-
derides, trimesters of Al Kane -1,2 -dill, I- hydroxy acid
and fatty acid; esters of hydroxy Masonic acid, fatty acid
and alcohol; trimesters of hydroxy acids, fatty acid and
05 fatty alcohol; trimesters of fatty acid, hydroxy acid and
dill.
Over the first coating, an overcoat or second
coating is provided which is: 1) amenable to being render-
Ed permeable in early portions of the gastrointestinal
10 tract, preferably within approximately the first hour of
entering the gastrointestinal tract; and 2) able to pro-
vent agglomeration or clumping of the coated microcopy-
sulks or micro spheres.
It is this combination of coatings (first and
15 second overreacting of the micro spheres) which permit the
dosage form to be successfully placed in a liquid carrier
vehicle for at least 35 days prior to ingestion. This
combination of coatings helps maintain dispersibility of
the dosage forms while physically retaining the there-
20 poetical active compound or active drug within the dosage form prior to actual ingestion of the liquid dosage
formulation.
Compounds useful for the second coating or
overreacting include: the prolamins, such as Zen, glib-
25 din, or harridan; also carotid; also starch and its derive-
lives; also cellulose derivatives, such as the dibasic
acid monster derivatives of cellulose including cell-
lose acetate phthalate and cellulose acetate succinate,
also cellulose derivatives such as carboxymethyl cell-
30 lose acetate, carboxymethyl ethyl cellulose, car boxy-
methyl hydroxypropyl cellulose acetate, carboxymethyl
cellulose Starkey acid, also cellulose ethers such as
ethyl cellulose. Compatible blends of any of the fore-
going can also be used.
-- 7 --
The second coating should be selected so as to
be generally nonsalable in the carrier liquid, however,
rendered permeable in the gastrointestinal tract. Van-
out means of rendering the second coating permeable can be
osemployed. For example, tube second coating can be pi
sensitive, meaning soluble in only a limited range of pi
i.e., alkaline soluble in the GO tract; or the second
coating can be broken down by enzymes such as lapses,
pro teases, or amalases, i.e., the second coating, can be
a protein which is broken down by any of various pro teases
in the gastrointestinal tract; or the second coating can
be a starch broken down by enzymes such as aimless within
the GO tract. The preferred materials for the second
coating or overreacting are Zen or cellulose acetate
15Phthalate .
Any common plasticizer such as deathly Thea-
late, tributyl citrate, tributyrin; Tristan, castor
oil, partially or fully acetylated monoglycerides or
bottle phthalyl bottle glycolate can be employed in either
200r both coatings to impart desired or what is deemed
suitable flexibility, workability or resiliency to the
coating. The plasticizer can also be used to modify the
permeability of the respective coating.
The dual coated micro spheres or dual coated
2scontrolled release dosage form can be dispersed in the
carrier or delivery liquid medium. While water may be used
as the carrier liquid it is preferred to add thickeners to
assure uniform dispersion. More preferred, since many
pharmaceutical drugs have a degree of water volubility,
awry liquid carriers which diminish the amount of available
water such as aqueous solutions of colloidal choirboy-
drapes or sugar syrups. Many suitable carrier liquids can
be employed, such as, by way of illustration and not
limitation, high fructose corn syrup, honey, sugar syrup,
Sweeney aqueous solution of carboxymethyl cellulose, glycerin,
gum Arabic ajar, or gelatin. Miscible combinations of
the foregoing are also possible. In the preferred embody-
-- 8 --mint, the delivery medium is chosen so as to reduce the
proportion of water available to leach the active drug
from the dual coated dosage form, but also to be palate
able to the recipient of the liquid dosage formulation.
05 Slightly acid carrier liquids are preferred since they
also tend to retard microbial growth. High fructose corn
syrup was found to be a particularly suitable delivery
medium as such syrup has only approximately 30% water and
is naturally acidic.
In general the liquid carrier is best selected
so as to be a poor solvent of the particular pharmaceutics
Sugar solutions and sugar syrups are useful as
the carrier liquid from the aspect of limiting the avail-
able water but also as a preservative.
Though any of the foregoing liquids can be used
as the carrier liquid in which the dual coated dosage forms
are dispersed, it is advantageous where possible to select
a carrier liquid such that the active drug held in the dual
coated dosage form is not soluble or only minimally soul-
bye in the carrier liquid.
In the preferred embodiment, the present in-
mention provides an improved delivery vehicle for con-
trolled release dosage forms, which dosage forms are
understood to include controlled-release matrix beads,
micro spheres, micro capsules, or reservoir type capsules
or devices, by enabling preparing of liquid formulations
of such dosage forms having a substantial shelf life.
Micro spheres, micro capsules, and matrix beads are pro-
furred dosage forms, especially in the size range of 15
microns to 7000 microns.
The microphones and controlled release dosage
forms useful for the purposes of being dual coated accord-
in to the invention can be prepared by any of several
known micro encapsulation processes or micro sphere or ma-
trip bead production processes including pan coating,
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pilling, granulation fluidization processes, pressing through fine mesh screens and other processes.
Though particularly suitable for controlled
release micro spheres package able and administrable in a
Lockwood formulation intended for young children or the
elderly, this invention can also be practiced with any of
the earlier-mentioned controlled release type dosage
forms. Also larger, relatively speaking, controlled-
release tablets, capsules, devices, spheres or matrix
libidos coated according to the present invention can pro-
vise dosage forms suitable for preparation in a liquid
formulation, for example, in veterinary applications,
where micro sizes become relative to the size of the
recipient.
The liquid suspension of dual coated controlled
release dosage forms according to this invention can be
prepared in advance in many cases as early as 35 days or
sooner before the intended day of administration of the
liquid formulation. Upon ingestion of the liquid dosage
formulation, the controlled release characteristics of
the dual coated micro spheres are expressed with active
dry release commencing in the upper gastrointestinal
tract and active drug release continuing at a uniform rate
thereafter for at least 8-12 or 24 hours.
The controlled release liquid dosage forum-
lotions of the present invention are particularly suit-
able for such drugs as theophylline, dimethylxanthine,
antihistamines, cold formulations, analgesics, amino acid
supplements, geriatric drugs such as sleeping aids and
blued pressure regulators, antidepressants such as lithe
I'm chloride, also potassium salts, and alkaloids such as
caffeine and codeine.
The following example serves to illustrate the
invention, however, the invention is not to be construed
assay limited thereto.
-- 10 --
EXAMPLE
Theophylline was selected to illustrate the
dual coated dosage form and liquid dosage formulation of
the present invention. Theophylline was selected to
osillustrate the scope of the invention since a suitable
liquid dosage formulation, especially one in which the-
ophylline is the therapeutically active compound, must
satisfy a particularly rigid controlled-release profile.
Theophylline is a representative alkaloid drug.
It is isometric with dimethylxanthine and the common alga-
fold, caffeine, differs from theophylline by one less
methyl group. Theophylline, typical of alkaloids, is
bitter.
Theophylline is used as an anti asthmatic but it
has an unpleasant taste and requires careful dose meat
surmount and administration to maintain therapeutic serum
concentrations. Especially with young children, the now
required every 4-6 hour round-the-clock dosing levels of
theophylline are difficult to administer and maintain.
cauldron often dislike the taste.
It is held by some in the field that theophyl-
line is a tissue irritant and thus is preferred to be
administered in an enteric release form.
Thus, the preferred controlled release liquid
2sdosage formulation containing theophylline according to
this invention should satisfy the rigid criteria of:
1) withhold release to the carrier liquid when
stored as a liquid formulation so as to have significant
shelf life, preferably at least 35 days;
2) begin release of the active drug 1 hour after
entering the gastrointestinal tract;
3) continue uniform sustained release of the
active drug for at least 8 to 24 hours.
It has been found that the liquid dosage forum-
3slation of the present invention is particularly ad van-
I
tageous for the administering of theophylline. A liquid dosage formulation sustaining theophylline release up to
12 or 24 hours according to this invention would be part-
ocularly beneficial to asthmatic children, would be easy to
administer because of the liquid carrier and its masking
of the unpleasant taste, and would require less frequent
administration.
With a stable shelf life in excess of 35 days,
the premixed liquid dosage formulation would be practical
for dispensing by pharmacies.
Examples of five commercially available con-
trolled release type dosage forms are illustrated below.
The active drug is theophyllinè in these preparations.
1. Aerolate0, 1, 2 and 4 grain capsules (Flex-
liming and Company, St. Louis, Missouri).
2. Theodore, 200 and 300 my scored tablets
(Key Pharmaceuticals, Inc., Miami, Florida)
3. Theodore Sprinkle, 50, 75, 125 and 200 my
strengths (Key Pharmaceuticals, Inc., Miami, Florida).
4. Slo-Phylline Gyro caps 60, 125 and 250 my
capsules (Downer Laboratories, Inc., Haverhill, Massachu-
sells).
5. Sister tablet (Reargue, Division of Pit-
zero Inc., New York, New York).
Based upon the release profile of these sup-
twined release type products, the Theodore scored tab-
lets and Slo-Phylline Gyrocaps when placed into apple-
sauce exemplify the typical "liquid dosage formulation"
available today. Tested for release of theophylline via
swarm levels it was found that after 1 hour, the Theodore
scored tablets had released 10% of their theophylline and
the Slo-Phylline Gyrocaps0had released 80~ of their the-
felon. The typical controlled release dosage form
; available today does not have any significant shelf life
inn an aqueous based carrier fluid since appreciable no-
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lease proceeds from the initial time of dispersion in the
carrier liquid.
Source of Typical Controlled Release Test Dosage Forms
Typical sustained release dosage forms in the
05 arm of spherical beads or micro spheres are readily ox-
twined from commercial sources. In this case, the micro-
spheres were obtained from Central Pharmaceuticals, Inc.,
110-128 E. Third Street, Seymour, Indiana. The following
analysis was provided:
10 Product 48.15~ Theophylline An hydrous sustained
Release Beads
-
Analyzed for Label Claim Found % of Claim
Theophylline An hydrous 48.15% 49.4% 102.6%
Release Rate:
I Method - US Dissolution Apparatus 2 operated at
50 RPM
Released in:
Limits
1 hour 10.1% 5.0-20.0%
2 hours 27.9~ 20.0-40.0
4 hours 61.0% 50.0-85.0
6 hours 79.3% NUT 65.0%
8 hours 89.1% NUT 85.0%
Process for Coating Controlled Release Test Dosage Forms
inn a fluidized bed process the above mentioned
controlled release test dosage forms in the form of sphere
teal beads containing theophylline were sprayed with a
solvent solution of Camille (Derek) which is a partially
hydrogenated cottonseed and soybean vegetable oil. This
30 oil has a Wily melting point of 97-101F and solid fat
index (SKI) values as follows: 50F = 69% mint 70F = 54%
mint 80F = 53% mint 92F = 22% mint 100F = 5% max.
- 13 -
he Camille coated beads were then coated either
with Zen or cellulose acetate phthalate (CAP). A pies-
ticizer was included to enhance the coating properties of
the Zen and CAP. With Zen, the plasticizer used was
05 Myvacet0 (Eastman Kodak) a distilled acetylated Mooney
glyceride. With cellulose acetate pthalate a bottle Thea-
lyl-butyl glycolate liquid sold as Sanitizer (Pfizer) was
used as a plasticizer.
The following types of coated dosage forms were
lo prepared for testing (all percents given are by weight).
Table 2
# 1 - uncoated dosage form
# 2 - dosage form coated with 17.7~ Camille
15 #-3 - dosage form coated with 17.7~ Roomily followed by 4.33
cellulose acetate phthalate
# 4 - dosage form coated with 17.7~ Roomily followed by
4.33% cellulose acetate phthalate containing 1.7
plasticizer
20 # 5 - dosage form coated with 17.7% Roomily followed by 4.0%
Zen containing Owe% plasticizer
# 6 - dosage form coated with 17.7% Roomily followed by 2.2%
Zen containing Owe plasticizer
# 7 - dosage form coated with 4.76~ Roomily followed by 2.37%
cellulose acetate phthalate containing 1.0% plasticizer
# 8 - dosage form coated with 4~78% cellulose acetate phthalate
containing 1.92~ plasticizer
# 9 - dosage form coated with 2.41% cellulose acetate
phthalate containing 0.97% plasticizer
30 lo - dosage form coated with 4.76% Camille
(All percentages are on the basis of total weight of
coated dosage form)
,;
. .
- 14 -
Four release tests (A thrum D below) were de-
signed to assess release characteristics of the various
coated dosage forms.
Assessment of Release to Liquid Carrier
05 (A) dosage form placed in a high fructose corn syrup
solution and theophylline release determined after 7
or 14 days.
(B) dosage form placed in a phosphate buffer (pi 6.0) and
release of theophylline determined after l, 3 and 7
days.
(C) dosage form placed in a phosphate buffer (pi 4.5) and
release of theophylline determined after 1, 3 and 7
days.
Assessment of Release Profile in Gastrointestinal Tract
15 (D) dosage form placed in simulated gastric fluid
(pi ~1.2) for 1 hour, followed by placement in
simulated intestinal fluid (pi -7.5) over the next 7
hours. Theophylline release was determined at 1, 2,
3, 4, 5, 6 and 8 hours.
In conducting the (B) and (C) in vitro release
studies, approximately 100 milligrams of selected dosage
forms were placed in a test tube containing 10 ml of the
phosphate buffer (either pi 6.0 or pi 4.5) test solution.
These studies were conducted at ambient temperature with
25 the test tube contents mixed via a Lab Quake test tube
rotator. At predetermined times, the test solution was
drawn off. Fresh test solution was then added back to the
test tube. The procedure of drawing off the test solution
was performed on days 1, 3 and 7. The test solutions
30 removed on days 1, 3 and 7 were filtered and refrigerated
until assayed for theophylline.
In conducting the (A) in vitro release study, the
principal difference was that high fructose corn syrup
(HFCS, Corn Sweet 42, Archer Daniel Midland Co.) was
;
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- 15 -
substituted as the test solution for the phosphate buffer.
Other aspects of this in vitro release study were similar
to those described for (B) and (C).
The (D) in vitro release study was similar to the
05 (B) and (C) in vitro release studies with the exception of
duration, temperature and test solution. All (D) in vitro
release studies were conducted at 37 C by placing the test
tunes on the Lab quake rotator in a thermostatistic-
ally-controlled oven. The test solution for this on vitro
10 release study was a simulated gastric fluid during the
first hour followed by a simulated intestinal fluid.
The simulated gastric fluid was prepared as
follows:
2.0 g of sodium chloride and 3.2 g of pepsin was
15 dissolved in 7.0 ml of hydrochloric acid and sufficient
water to make a 1000 ml solution. This test solution has
a pi of about 1.2.
The simulated intestinal fluid was prepared as
follows:
6.8 g of monobasic potassium phosphate was disk
solved in 250 ml of water. With stirring, 190 ml of 0.2
N sodium hydroxide was added along with 400 ml of water.
10 g of pancreatic was then added with stirring. The pi
of the resulting solution was adjusted to a pi of 7.5 + Al
25 by the addition of 0.2 N sodium hydroxide, then the so-
lotion was diluted with water to 1000 ml.
Theophylline release in the simulated gastric
fluid test solution followed by simulated intestinal fluid
test solution was determined at the end of 1, 2, 3, 4, 5,
6 and 8 hours.
In all the in vitro release studies A through D,
theophylline was assayed by a reverse phase high pressure
liquid chromatography (HPLC) technique as set forth by L.C.
Franconi et. at., "Determination of Theophylline in Plasma
35 Ultra filtrate by Reversed Phase High Pressure Liquid Cry-
matography," Anal. Chum., 48: 372, 1976.
- 16 -
The results of the (A) in vitro release study
(Table 3) show that when the dosage form is placed in high
fructose corn syrup, HFCS, an acidic environment, several
dosage forms show extremely low levels of theophylline
05 release. In particular, type #4 dosage form released only
0.2 percent of the available theophylline over a 14-day
period. The uncoated dosage form under these same condo-
lions and duration released 14.8~ of the available the-
ophylline. Another four types #'s 5, 7, 8 and 10 exhibited
10 less than 1 percent release after 7 days. The reduced
amount of theophylline released is due primarily to the
coatings placed over the controlled release dosage forms.
The low percentage of water in the HFCS, i.e., 29 percent,
tends to further minimize the amount of theophylline which
15 is released. Theophylline volubility in water = 8.3 mg/ml.
The results of the (B) and (C) in vitro release studies
(Tables 4 and 5) verify the importance of the liquid
carrier pi in which the dosage form will be eventually
formulated. For instance, in Table 4, the lowest per-
20centage of theophylline release from the #4 type dosage form was 47.1%. However, in Table 5, when this same type
#4 dosage form was placed in an acidic environment (pi
4.5), the theophylline release had dropped to 1.8%. Add-
tonally, the dosage form overreacted with Kaomel~-CAP
produced the least amount of theophylline release. The
importance of these two coatings, i.e., Camille and CAP,
is clearly established if compared with dosage form types
#8 and #9 (See Table 5).
-- 17 --
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Since only a very small percentage of the-
felon release had occurred over a 7 day period with the
type #4 dosage form in an acidic environment, this same
type dosage form was followed for 35 days in a pi 4.5
05 phosphate buffer solution. In this study, the total
theophylline released over a 35 day period was determined
to be 5.85 percent (See Table 6). This figure is believed
to be upwardly biased since the test solution was changed
every 7 days with fresh test solution. This changing of
10 solution increased the concentration gradient between the
coated dosage forms and the liquid environment. Absent
the solution changing, the actual amount of theophylline
released would approximate 1.3 percent. This is based
upon the fact that the actual amount of theophylline
15 released at the end of each 7 day period approximated
0.4 - 0.5 my. The total amount of theophylline originally
available for release from the type I pill was 39.3
milligrams, i.e., 0.5 39.3 = 1.3 percent.
This latter study represents a situation in
20 which the medium is essentially 100% water. Thus, even
under these severe test conditions, very little theophyl-
line was released. Thus, the importance of these coat-
ins, as they relate to the pi of the liquid environment,
is demonstrated.
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-- 21 --
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It can be seen from Table 7 that the dosage forms
overreacted with cellulose acetate phthalate alone do not
yield acceptable controlled release characteristics as
such dosage forms release a high burst of theophylline in
the second hour of the test. The release rates of the CAP
alone coated dosage forms exceed even that of the uncoated
dosage forms. Camille alone as a coating was found to be
unworkable for several reasons including problems of
clumping or aggregation. Uniform dosage levels ofKaomel~
alone coated dosage forms were difficult to measure and
the clumping tended to reduce available surface area thus
giving rise to questions as to reproducibility of release
profiles. The present invention unexpectedly requires
dual coated dosage forms to provide a liquid suspension of
controlled release formulations having substantial shelf
life that retains its controlled release characteristics.
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