Note: Descriptions are shown in the official language in which they were submitted.
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MICRO-OSMOTIC CONTROLLED DRUG DELIVERY SYSTEMS
BACKGROUND OF THE INVENTION
The invention relates to the field of osmotic release systems for the
controlled
release of a'therapeutic agent. Osmotic release systems facilitate the
controlled release of
a medicament from a dosage form based on a change in osmotic pressure in the
dosage
form. Osmotic release systems are useful for the delivery of both poorly
soluble and
highly soluble therapeutic agents.
SUMMARY OF THE INVENTION
In accordance with the current invention, a micro-osmotic controlled drug
delivery system has been developed. The micro-osmotic system contains the
following
components: a micro-osmotic core, a drug component, and, optionally, a
controlled
release matrix and/or coating.
The micro-osmotic core contains at least one osmotic agent and, optionally, a
swelling agent and/or a gelling agent. Osmotic agents facilitate the
penetration of
aqueous biological fluids into the micro-osmotic core. Osmotic agents include,
for
example, sorbitol, mannitol, xylitol, sodium chloride or any other such highly
soluble and
pharmaceutically acceptable excipient. Preferred osmotic agents include, for
example,
the following osmotic agents: spray dried sorbitol, particularly Sorbitol
Instant (EM
Industries, Hawthorne, New York), which has a surface area of ~lmZ/g; spray
dried
mannitol; mannitol with a polymorphic composition (dry state) that contains
not less than
about 85% of the "8" form of mannitol; a combination of sorbitol-mannitol-
xylitol,
preferably with sorbitol z 90%, mannitol Z 4%, and xylitol z4%, such as
described in DE
. 196 47 282 A1, P96 47 282 - DE and WO 44 39 858, PCTJEP95/04059.
The micro-osmotic core may also optionally comprise a swelling agent. The
' swelling agent expands in volume when contacted by aqueous biological
fluids, thereby
changing the volume of the micro-osmotic core. A swelling agent preferably is
capable
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of swelling to a volume that is many times its volume in the dry state.
Preferred swelling
agents include, for example, sodium starch glycollate, crosscarmellose sodium,
cellulose,
and microcrystalline cellulose.
The micro-osmotic core may also optionally comprise a gelling agent. The
S gelling agent functions to maintain the integrity of the swelling agent and
thereby
functions to maintain the integrity of the micro-osmotic core. The gelling
agent is
preferably a water soluble polymer. Preferred gelling agents include, for
example,
hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC),
polyvinylpyrrolidone (PVP) and its derivatives, gums - tragacanth, accacia,
guar,
carageenan, and other carbohydrate derived gums, alginic acid and its
derivatives, and
carbomers.
The micro-osmotic core is in the form of small particles, with diameter ranges
of
between about 2 ~cm to about 3000 ~cm, preferably 200 ~m about to about 3000
Vim, and
more preferably about 200 ~cm to about 1500 ~cm. The particles may be
miniature tablets
such as, for example, may be formed using a water soluble lubricant such
as.PEG 8000.
The micro-osmotic core may also be extruded and spheronized into small spheres
and/ or
spray agglomerated into particles. The osmotic agent/swelling agent/gelling
agent may
be combined in weight ratios ranging from 10010/0 to 0.05/99.9/0.05 to
99.9/0.05/0.05 to
0.05/0.05/99.9. Preferred ratios of osmotic agent/swelling agent/gelling agent
are the
following: 1/8/1, 217/1, 3/6/1, 4/5/1, 6/212, 7/1/2, 8/1/1, 9/0.5/0.5, and
5/4/1.
The micro-osmotic cores of the invention are coated with a drug component to
obtain loaded cores. Coated, as used herein, refers to any physical contact
between the
drug component and the micro-osmotic core. For example, micro-osmotic cores
may be
fully coated with the drug component, partially coated with the drug
component, or
impregnated with the drug component. Loaded cores preferably have diameter
ranges of
between about 2 ~m to about 3000 ~cm, more preferably about 200 ~m to about
3000 Vim,
and most preferably about 200 ~cm to about 1500 ~cm. The drug component
comprises at
least one therapeutic agent. The therapeutic agent in the drug component rnay
be, for
example, in the form of a solid, a solid-state solution, a solid-state
solution-dispersion, a
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microdisperse system, a solution-suspension (e.g. aqueous, alcoholic, or
hydroalcoholic),
or any combination thereof. The therapeutic agents may be combined with select
excipients andlor binders. The solution-suspension form of the therapeutic
agent may
optionally include a hydrophilic agent such as HPMC, HPC, PVP, sorbitol,
and/or natural
gums (for example, accacia) in addition to water, alcohol, or a hydroalcoholic
system.
A solid-state solution, as used herein, refers to a solution of the
therapeutic agent
in solid form. A solid-state solution of the therapeutic agent is
characterized by the lack
of a melting point peak at the melting point of the therapeutic agent,
indicating the
absence of the solid state of the therapeutic agent. A solid state solution-
dispersion, as
used herein, is a system in which part of the therapeutic agent is in the form
of a solid-
state solution and part of the therapeutic agent is in the form of a finely
dispersed solid.
Preferably, greater than 1 % of the total therapeutic agent content exists in
solution in
the system, in either the solid, semi-solid, or liquid phases. The system is
also
characterized in that at least one therapeutic agent can exist as a solid
dispersion. Any
portion of the therapeutic agent which exists as a solid dispersion preferably
has a
panicle size distribution wherein the diameter of about 90% of the particles
is less than
aboutl0~.
For a solid-state solution-dispersion, the solubilized therapeutic
agent/dispersed
therapeutic agent ratio is in a range from 1/99 to 100/0. Preferably, about
30% to
about 100 % of the therapeutic agent exists in solution, and more preferably,
about 60 %
to about 90 % of the therapeutic agent exists in solution. The ratio of the
amount of
therapeutic agent present in the form of a solid-state solution to the amount
present in the
form of solid dispersion can be easily ascertained by the use of techniques in
thermal
analysis such as Differential Scanning Calorimetry (DSC), Thermal Gravimetric
Analysis
(TGA), and Differential Scanning Microcalorimetry. The crystallinity of the
therapeutic
agent is easily determined by X-ray diffraction.
One example of a solid-state solution-dispersion system, particularly for
therapeutic agents having poor water solubility, comprises a mixture of
saturated
polyglycolyzed glycerides (for example, Gelucire~, available from Gattefosse),
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polyoxypropylene-polyoxyethylene block copolymer (for example, Pluronic~NF
surfactants, available from BASF), and a therapeutic agent, as described, for
example, in
U.S. Patent Application No. 09/050913 and in U.S. Provisional Patent
Application Nos.
60/080163, 60/085417,60/085333, and 60/092767. The polyglycolyzed glycerides
component of the pharmaceutical carrier composition may include all grades of
the
saturated and unsaturated polyglycolyzed glycerides, preferably polyglycolyzed
glycerides with a hydrophilic-lipophilic balance (HLB) > 10. Preferred
polyglycolyzed glycerides include, for example, Gelucire ~ 44/13 and Gelucire
50/13. The mixture may also include all grades of polyoxypropylene-
polyoxyethylene
block co-polymer, preferably polyoxypropylene-polyoxyethylene block co-
polymers
with a HLB > 10. Preferred polyoxypropylene-polyoxyethylene block co-polymers
include, for example, Pluronic~ L44, Pluronic~ F68, Pluronic~ F108, and
Pluronic~
F127. The polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-
polymer may be combined in weight ratios ranging from about 0.10/99.9 to about
99.9/0.10. The preferred ratios are 1/9, 2/8, 3/7, 4/6, 6/4, 7/3, 8/2, 9/1 and
5/5. The
combination of saturated polyglycolyzed glycerides/polyoxypropylene-
polyoxyethylene
block co-polymer preferably has a melting point in the range of about
30°C to about
70°C, and more preferably about 50°C to about 70°C. When
a polyglycolyzed
glycerides/polyoxypropylene-polyoxyethylene block co-polymer combination is
employed, the combination is present in the final composition of the drug
component in
an amount of about 0.10% to about 99.9%, and preferably about 5% to about 75%.
Therapeutic agents are present in the final composition of the drug component
in an
amount of about 0.10% to about 99.9%, preferably about 5% to about 75%.
Examples of therapeutic agents that may be used in conjunction with this
invention include the following: dihydropyridine compounds, including for
example,
nifedepine, felodipine, nicardipine; cyclopeptides, including for example
cyclosporine;
omperazol; spironolactone; furosemide; terbutaline; riboflavin; gemfibrozi;
indomethacin; ibuprofen; phenytoin; and glyburide. Additionally, any
therapeutic
agent with an intrinsic solubility of less than about 10.0 g/L and having
therapeutic
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activity in any of the following areas are contemplated as part of this
invention: activity
in the cardiovascular system; immunosuppressive activity; cholesterol lowering
activity; anti-hypertensive activity; anti-epileptic activity; hormonal
activity;
hypoglycemic activity; anti-viral activity; anti-histaminic activity; nasal
decongestant
activity; anti-microbial activity; anti-arrthrytic activity; analgesic
activity, anti-
mycobacterial, anti-cancer activity, diuretic activity, anti-fungal activity,
anti-parasitic
activity, activity as a central nervous system (CNS) stimulant, activity as a
CNS
depressant, activity as a 5-HT inhibitor, anti-schizophrenia activity, anti-
alzheimer
activity, anti-psoriatic activity, anti-ulcer activity, activity as a proton
pump inhibitor,
anti-asthmatic activity, activity as a bronchodialator, and thrombolytic
activity. The
therapeutic agent may be, for example, a protein, a peptide, a cyclopeptide, a
steroid
molecule, a vitamin, an oligonucleotide, or any small or large molecule, or
any
combination of the foregoing.
In addition to the therapeutic agent or agents, the drug component may
optionally comprise excipients. Excipients preferably comprise about 5 % to
about
95 % by weight of the final composition of the drug component, and more
preferably
about 10%o to about 70%. Examples of suitable excipients include, but are not
limited
to, the following: ascorbyl palmitate; tocopheryl acetate; glycerol; glyceryl
monooleate; glyceryl monosterate; glyceryl palmitosterate; triglycerides;
diglycerides;
monoglycerides; stearic acid; magnesium stearate, talc, diesters of
polyethylene glycol
(PEG); monoesters of PEG; polyethylene glycol; glyceryl polyoxyethylene fatty
acid
esters; glyceryl polyoxyethylene polyethylene glycol fatty acid esters and
ethers;
polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives;
polyoxyethylene
sorbitan fatty acid esters; polyoxyethylene sterates; polyvinyl alcohol;
sodium starch
glycollate; sorbitan fatty acid esters; polyoxyl sterates; polyethylene glycol
hydroxysterate; polyoxyethylene alcohols; anionic; cationic; amphiphilic
compounds;
lecithins; phospholipids; carbohydrates, including for example, lactose,
maltodextrins,
sucrose, and starch; polyols, including for example, sorbitol, mannitol, and
xylitol;
microcrystalline cellulose; vitamins, including for example, ascorbic acid and
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niacinamide; bioflavonoids, including for example, quercetin, isoquercetin,
naringin,
rutin, etc.; and inorganic compounds, including for example, calcium
carbonate,
dicalcium phosphate, and any combinations of the above mentioned materials.
The micro-osmotic cores that are coated with a drug component (loaded cores),
can be either coated with a suitable polymeric coating and/or combined with a
polymer
matrix system. The polymer coating or the polymer matrix may serve to modify
the .
release profile of the therapeutic agent from the loaded cores. The polymer
coating may
comprise, for example, the following: hydrophilic polymers such as, for
example HPMC,
HPC, derivatives of cellulose, derivatives of starch, PVP and PVP derivatives,
and
carbomers; water insoluble polymers such as, for example, ethyl cellulose,
cellulose
acetate, polymethacrylate polymers (for example, Eudragit~ polymers, ) and
pseudolatex
dispersions of the above; enteric polymers such as, for example, shellac,
cellulose acetate
phthalate; plasticizers such as, for example, dibutyl sebecate, triacetin,
acetyl tributyl
phthalate; and pearlescent pigments such as, for example, the CandurinTM line
of
pigments (EM Industries, Hawthorne, New York). Coating of the loaded cores can
be
performed using pharmaceutical techniques that are well known in the art,
including
techniques such as wurster coating, rotor coating, and/or pan coating.
The polymer matrix comprises at least one hydrophilic polymer such as, for
example, cellulose and its derivatives, including, for example, HPMC, HEC,
Carbomers
(e.g. Carbopol P934, Carbopol P974), and alginic acid and its derivatives. The
hydrophilic polymers of the polymer matrix preferably have molecular weights
of
between about 100 to about 4,000,000. The hydrophilic polymers are also
preferably
combined with at least one hydration enhancer which allows for faster
hydration of the
hydrophilic polymer. Hydration enhancers include, for example, sorbitol,
mannitol,
xylitol, and microcrystalline cellulose, and any combination thereof. A
preferred
hydrating enhancer is a specialized spray agglomerated form of sorbitol
(commercially
available as Sorbitol Instant, EM Industries, Hawthorne, New York) which has a
surface
area of 1m2/g. Hydrophilic polymers of different molecular weights and
different
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chemical natures may be combined to achieve the desired release profile for
the
therapeutic agent.
The loaded cores and the polymer matrix may be dry blended and then granulated
by using a suitable solvent (e.g. aqueous and/or organic) and/or processed to
form beads
or spheres, or compressed into tablets using suitable lubricants. Suitable
lubricants for
compressing the dry blended mixture of the loaded cores and the polymer matrix
include,
for example, sodium stearyl fumarate, magnesium sterate, PEG 8000. A flow
promoter
such as, colloidal silicon dioxide, may also be employed as part of the
compression step.
The product from the above processes, which comprises loaded cores, both
coated
and uncoated, optionally blended with a polymeric matrix to form a dry blend,
and
optionally further processed to form granules, beads, spheres or tablets, may
be further
processed into final dosage forms as follows. As one example, granules,
spheres, beads
or the dry blend may be compressed into tablets, and the tablets may
optionally be coated
with a polymeric coating to modify the release profile of the therapeutic
agent. The
polymeric coating is essentially as described above. As another example,
beads, spheres,
or granules may be coated with a polymeric coating essentially as described
above. The
coated beads, spheres or granules may then be encapsulated into capsules or
compressed
into tablets, with the use of suitable pharmaceutical excipients.
It is also contemplated as part of this invention that a final dosage form
rnay
comprise more than one type of loaded core. For example, loaded cores
containing
same therapeutic agent but having different release profiles may be
incorporated into
the final dosage formulation. Different release profiles for loaded cores
containing the
same therapeutic agent may be obtained, for example, by varying the content of
the
micro-osmotic core or the polymeric coating of the loaded cored.
Alternatively, loaded
cores having different therapeutic agents may also be incorporated into the
same final
dosage formulation.
The invention also relates to a method of manufacturing a pharmaceutical
composition. The method comprises the steps of providing a micro-osmotic core;
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coating the micro-osmotic core with a drug component to form loaded cores, and
optionally, formulating the loaded cores into final dosage forms as described
above.
The invention also relates to a method for delivering one or more therapeutic
agents to a physiologic target site. The method comprises the steps of
providing a
pharmaceutical composition according to the invention and introducing a
pharmaceutically effective amount of the pharmaceutical composition to a
physiologic
target site. The introduction of the pharmaceutical composition to the
physiologic
target site may be accomplished, for example, by administration topically,
subcutaneously, intramuscularly, intraperitoneally, nasally, pulmonarily,
vaginally,
rectally, aurally, orally or ocularly. A preferred method for delivering at
least one
therapeutic agent to a physiologic target site that is contemplated by this
invention is
through oral delivery.
g~FF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the in vitro release profile of felodipine from
tablets formed according to example 17.
Figure 2 is a graph showing the in vitro release profile of felodipine from
tablets formed according to example 18.
Figure 3 is a graph showing the in vitro release profile of felodipine from
tablets f4rmed according to example 19.
Figure 4 i's a graph showing the in vitro release profile of felodipine from
tablets formed according to example 20.
Figure S is a graph showing the in vitro release profile of felodipine from
tablets formed according to example 21.
Figure 6 is a graph showing the in vitro release profile of felodipine from
tablets formed according to example 22.
Figure 7 is a graph showing the in vitro release profile of felodipine from
tablets formed according to example 23.
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Without further elaboration, it is believed that one skilled in the art can,
using the
preceding description, utilize the present invention to its fullest extent.
The following
' prefer ed specific embodiments are, therefore, to be construed as merely
illustrative, and
not limitative of the remainder of the disclosure.
EXAMPLES
In the following examples, all parts and percentages are by weight unless
otherwise indicated.
For examples 17-23 below, the following components were employed.
1. PruvTM - (sodium stearyl fumarate) (available from Mendell).
2. AvicelT"' PH200 - (microcrystalline cellulose NF) (available from FMC).
3. Sorbitol Instant P300 - (Sorbitol NF) (available from Merck KGaA).
4. MethocelT"s E4M Premium CR - (hydroxypropylmethyl cellulose NF) (available
from
Dow Chemical).
5. MethocelTM K100 M - (hydroxypropylmethyl cellulose NF) (available from
Dow Chemical).
6. TriacetinT"' - (glyceroltriacetate) (available from Spectrum Quality
Products).
7. Eudragit~ NE 30 D - (30% aqueous dispersion of polyacrylate copolymers)
(available
from Roehm).
8. Eudragit~ L 30 D - (30% aqueous dispersion of methacrylic acid/methacrylate
copolymers) (available from Roehm).
9. PVP 30 - (polyvinylpyrrolidone, MW: 44,000-54,000) (available as Kollidon~
30
from BASF)
10. Gelucire~ 50/13 - (saturated polyglycolized glycerides of hydrogenated
vegetable oil
consisting glycerides and PEG-esters) (available from Gattefosse).
11. Pluronic~ F 68 - (polyoxy propylene-polyoxy ethylene block copolymers)
(available
from BASF)
Example 1: Manufacture of the micro-osmotic cores.
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Micro-osmotic cores may be manufactured by any number of techniques known
in the art, using a variety of materials. A few of these techniques and
materials are as
follows:
( 1 ) crystalline or spray agglomerated sorbitol are employed as the micro-
osmotic
core;
(2) sorbitol, sodium starch glycollate, and HPMC are combined and compressed
into miniature tablets (for example, a diameter < 1 mm) using PEG 8000 as a
lubricant;
(3) sorbitol powder and sodium starch glycollate are combined, and the mixture
is
extruded and spheronized into spheres;
(4) sodium starch glycollate is spray agglomerated onto sorbitol.
Micro-osmotic cores may be made using any of the above methods or using any
other techniques that are well known in the art, including granulation.
Example 2: Manufacture of the therapeutic agent component as a solid state
solution-dispersion.
A mixture of polyglycolyzed glycerides and polyoxypropylene-polyoxyethylene
block copolymer are heated to 20°C above the melting point
(~50°C). The therapeutic
agent is added gradually to the molten mixture. The therapeutic agent is
preferably
milled to a particle size range such that the diameter of at least about 90%
of the particles
is less than about 75 microns. The mixture is maintained at 20°C above
the melting point
of the polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-
polymer
mixture. The ratio of the polyglycolyzed glycerides/polyoxypropylene-
polyoxyethylene
block co-polymer is selected to facilitate solubilization of > 1% and
preferably 30-100%
of the therapeutic agent in the mixture.
Example 3: Controlled release tablets containing I~Tifedepine.
_ Ingredients: Quantities {mg/Tab): Application
1. Sorbitol Instant P300 50 osmotic core
2. Nifedepine, USP 90 active
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3. Gelucire 50// 3 90 excipient
4. Pluronic F68 90 excipient
5. HPMC E4M CR Grade 300 hydrophillic polymer
6. Sorbitol Instant P30075 hydration enhancer
7. Microcrystalline Cellulose7~ hydration enhancer
8. Magnesium Stearate 6.8 lubricant
Sorbitol Instant was used as an osmotic core. Gelucire 50/13, Pluronic F68,
and
Nifedepine were processed together to yield a drug component having
IvTifedepine as the
therapeutic agent in a solid state solution-dispersion. The drug component was
then
spray congealed onto Sorbitol Instant. The loaded cores as manufactured above
were
blended with a polymeric matrix containing Sorbitol Instant P300, HPMC E4M CR
Grade, microcrystalline cellulose, and magnesium stearate. Controlled release
tablets
were obtained by compression of the mixture of the loaded cores with the
polymeric
formulation.
Example 4: Controlled
release tablets containing
Felodipine.
Ingredients: Quantities (mglTab):Application:
1. Sorbitol Instant P300SO osmotic agent
2. Sodium starch glycollate20 swelling agent
3. Felodipine, USP 90 active
4. Gelucire SO/13 90 excipient
5. Pluronic F68 90 excipient
6. HPMC E4M CR Grade 300 hydrophillic polymer
7. Sorbitol Instant P30075 hydration enhancer
8. Microcrystalline Cellulose75 hydration enhancer
9. Magnesium Stearate 6.8 lubricant
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Sorbitol Instant P300 and sodium starch glycollate were combined into a micro-
osmotic core. Gelucire 50/13, Pluronic F68, and felodipine were combined to
yield drug
component having felodipine in a solid-state solution. The drug component was
then
spray congealed onto the micro-osmotic core. The loaded cores as manufactured
above
S were then blended with Sorbitol Instant P300, HPMC E4M CR Grade,
microcrystalline
cellulose, and magnesium stearate. Controlled release tablets were obtained by
compression of the mixture of the loaded cores with the polymeric formulation.
Example 5: Controlled
release tablets
containing Phenytoin.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent
P300
2. Sodium starch glycollate20 swelling agent
3. HPMC E4M 10 gelling agent
4. Phenytoin, USP 95 active
5. Gelucire 50/13 90 excipient
6. Pluronic F68 90 excipient
7. HPMC K100 Grade 300 hydrophillic polymer
8. Sorbitol Instant 150 hydration enhancer
P300
9. Magnesium Stearate 6.8 lubricant
Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed
together into a micro-osmotic core. Gelucire SO/13, Pluronic F68, and
Phenytoin are
processed together to yield a solid state solution of Phenytoin in the matrix.
This drug
system is spray congealed onto the micro-osmotic core. The drug system micro-
osmotic
cores as manufactured above are blended with Sorbitol Instant P300, HPMC E4M
CR
Grade, microcrystalline cellulose, and magnesium stearate. Controlled release
tablets are ,
compressed with the above formulation.
Example 6: Controlled release tablets containing indomethacin.
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Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant SO osmotic agent
P300
2. Sodium starch glycollate20 swelling agent
3. HPMC E4M 10 gelling agent
4. Indomethacin, USP 100 active
5. PVP 90 excipient, binder.
6. HPMC K100 Grade 300 hydrophillic polymer
7. Sorbitol Instant 150 hydration enhancer
P300
8. Magnesium Stearate 6.8 lubricant
Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed
together into a micro-osmotic core. PVP, and Indomethacin are processed
together to
yield a suspension in ethanol. This drug system is spray coated onto the micro-
osmotic
core. The drug system micro-osmotic cores as manufactured above are blended
with
Sorbitol Instant P300, HPMC E4M CR Grade, microcrystalline cellulose, and
magnesium
IS stearate. Controlled release tablets are compressed with the above
formulation.
Example 7: Controlled
release tablets
containing Chlorpheniramine
maleate.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent
P300
2. Sodium starch glycollate20 swelling agent
3. HPMC E4M 10 gelling agent
4. Chlorpheniramine 10 . active
maleate
5. PVP 20 excipient, binder
6 HPMC K100 Grade 300 hydrophillic polymer
7. Sorbitol Instant 150 hydration enhancer
P300
8. Microcrystalline 6.8 lubricant
Stearate
~
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Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed
together into a micro-osmotic core. PVP and chlorpheniramine maleate are
processed
together to yield a solution in water. This drug system is spray coated onto
the micro-
osmotic core. The drug system micro-osmotic cores as manufactured above are
blended
with Sorbitol Instant P300, HPMC E4M CR Grade, microcrystalline cellulose, and
magnesium stearate. Controlled release tablets are compressed with the above
formulation.
Example 8: Controlled
release tablets containing
Diltiazem hydrochloride.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P300160 osmotic agent
2. Sodium starch glycollate40 swelling agent
3. HPMC E4M 20 gelling agent
4. Diltiazem hydrochloride300 active
p~rp 60 excipient, binder
6 Ethyl Cellulose dispersionq.s. hydrophobic polymer
7. Dibutyl sebecate q.s. plasticizer
8. Talc q.s. anti-caking agent
Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed
together into a micro-osmotic core. PVP and diltiazem hydrochloride are
processed
together to yield a solution in water. This drug system is spray coated onto
the micro-
osmotic core. The drug system micro-osmotic cores as manufactured above are
coated
with ethyl cellulose dispersion plasticized with dibutyl sebecate. Controlled
release
tablets are compressed with the above formulation.
Example 9: Capsules containing controlled release pellets containing
Chlorpheniramine maleate.
Ingredients: Quantities (mg/Tab): Application:
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1. Sorbitol Instant P300SO osmotic agent
2. Sodium starch glycollate20 swelling agent
. 3. pVp 10 gelling agent
4. Chlorpheniramine maleate10 active
S S. PVP 20 excipient, binder
6 Eudragit RS 30D dispersionq.s. hydrophobic polymer
7. Dibutyl sebacate q.s. plasticizes
8. Talc q.s. anti-caking agent
Sorbitol Instant P300,
HPMC E4M and sodium
starch glycollate
are processed
together PVP and chlorpheniramine maleate
into are processed
a
micro-osmotic
core.
together This drug system is spray coated
to onto the micro-
yield
a
solution
in
water.
osmo tic core. The drug
system micro-osmotic
cores as manufactured
above are coated
with
Eudragit
RS
30D
(polymethacrylate
copolymer)
dispersion
plasticized
with
dibutyl
sebecate. are encapsulated into capsules.
Controlled
release
pellets
Example 10: Controlled
release tablets containing
Nifedepine.
Ingredients: Quantities (mg/Tab): Application:
1. Sorbitol Instant P30050 osmotic agent
2. Sodium starch glycollate20 swelling agent
3. HPMC E4M 10 gelling agent
4. Nifedepine, USP 90 active
5. PVP 90 excipient, binder
6 Locust bean gum - 175 hydrophillic polymer
7. Xanthan Gum 175 hydrophillic polymer
8. Sorbitol Instant P3001 SO hydration enhances
9. Calcium Chloride 25 crosslinking agent
10. Magnesium Stearate 6.8 lubricant
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Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed
together into a micro-osmotic core. PVP and Nifedepine are processed together
to yield a
suspension in ethanol. This drug system is spray coated onto the micro-osmotic
core.
The drug system micro-osmotic cores as manufactured above are blended with
Sorbitol
Instant P300, locust bean gum, Xanthan gum, calcium chloride, and finally with
magnesium stearate. Controlled release tablets are compressed with the above
formulation.
Example 11: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab): Application:
1. Sorbitol Instant P300 50 osmotic agent
2. Sodium starch glycollate 20 swelling agent
3. Nifedepine, USP 90 active
4. PVP 90 excipient, binder
5. HPMC K100 Grade 300 hydrophillic polymer
6. Sorbitol Instant P300 150 hydration enhances
7. Ethyl cellulose 100 hydrophobic polymer
8. Triacetin 25 plasticizes
9. Magnesium Stearate 6.8 lubricant
Sorbitol Instant P300 and sodium starch glycollate are processed together into
a
micro-osmotic core. PVP and Nifedepine are processed together to yield a
suspension in
ethanol. This drug system is spray coated onto the micro-osmotic core. The
drug system
micro-osmotic cores as manufactured above are blended with Sorbitol Instant
P300,
HPMC K100 Grade and granulated with a granulating solvent composed of ethyl
cellulose and Triacetin, dried, delumped and finally combined with magnesium
stearate.
Controlled release tablets are compressed with the above formulation.
Example 12: Controlled release tablets containing Nifedepine.
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WO 99/63971 PCT/US99/13223
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Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P30050 osmotic agent
' 2. Sodium starch glycollate20 swelling agent
3. Nifedepine, USP 90 active
4. PVP 90 excipient, binder
S. HPMC K100 Grade 300 hydrophillic polymer
6. Sorbitol Instant P300150 hydration enhances
7. Ethyl cellulose 100 hydrophobic polymer
8. Triacetin 25 plasticizes
9. HPMC E4M 10 hydrophillic polymer
10 Magnesium Stearate 6.8 lubricant
Sorbitol Instant P300 and sodium starch glycollate are processed together into
a
micro-osmotic core. PVP and Nifedepine are processed together to yield a
suspension in
ethanol. This drug system is spray coated onto the micro-osmotic core. The
drug system
micro-osmotic cores as manufactured above are blended with Sorbitol Instant
P300,
HPMC K100 Grade and granulated with a granulating solvent composed of ethyl
cellulose; HPMC E4M, and triacetin, dried, delumped and finally combined with
magnesium stearate. Controlled release tablets are compressed with the above
formulation.
Example 13: Controlled
release tablets containing
Nifedepine.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P30050 osmotic agent
2. Sodium starch glycollate20 swelling agent
3. Nifedepine, USP 90 active
4. PVP 90 excipient, binder
S. HPMC K100 Grade 300 hydrophillic polymer
6. Sorbitol Instant P3001 SO hydration enhances
CA 02301042 2000-02-10
~'O 99!63971 PCT/US99/13223
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7. Ethyl cellulose 100 hydrophobic polymer
8. Triacetin 25 plasticizer
9. HPMC E4M 10 hydrophillic polymer
10. Magnesium Stearate 6.8 lubricant
S Sorbitol Instant P300 and sodium starch glycollate are processed together
into a
micro-osmotic core. PVP and Nifedepine are processed together to yield a
suspension in
ethanol. This drug system is spray coated onto the micro-osmotic core. The
drug system
micro-osmotic cores as manufactured above are blended with Sorbitol Instant
P300,
HPMC K100 Grade and granulated with a granulating solvent composed of ethyl
cellulose and triacetin, dried, delumped and finally combined with magnesium
stearate.
Controlled release tablets are compressed with the above formulation. These
tablets are
coated with a semi-permeable polymer coating system composed of ethyl
cellulose,
HPMC E4M, and triacetin.
Example 14: Controlled
release tablets
containing Nifedepine.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent
P300
2. Sodium starch glycollate20 swelling agent
3. Nifedepine, USP 90 active
4. PVP 90 excipient, binder
5. HPMC K100 Grade 300 hydrophillic polymer
6. Sorbitol Instant 150 hydration enhancer
P300
7. Eudragit NE 30D 100 hydrophobic polymer
8. Dibutyl sebecate 25 plasticizer
9. HPMC E4M 10 hydrophillic polymer
10. Magnesium Stearate 6.8 lubricant
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WO 99/63971 PCTNS99/13223
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Sorbitol Instant P300 and sodium starch glycollate are processed together into
a
micro-osmotic core. PVP and Nifedepine are processed together to yield a
suspension in
ethanol. This drug system is spray coated onto the micro-osmotic core. The
drug system
micro-osmotic cores as manufactured above are blended with Sorbitol Instant
P300,
HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit
NE
30D (polymethacrylate copolymer dispersion) and triacetin, dried, delumped and
finally
combined with magnesium stearate. Controlled release tablets are compressed
with the
above formulation. These tablets are coated with a semi-permeable polyner
coating
system composed of Eudragit NE 30D (polymethacrylate copolymer dispersion),
HPMC
E4M and Triacetin.
Example 15: Controlled release
tablets containing Verapamil
hydrochloride.
Ingredients: Quantities (mg/Tab):
Application:
1. Sorbitol Instant P300 220 osmotic agent
2. Sodium starch glycollate 40 swelling agent
3. Verapamil hydrochloride 240 active
4. PVP 60 excipient, binder
5. HPMC K100 Grade 300 hydrophillic polymer
6. Sorbitol Instant P300 50 hydration enhancer
7. Eudragit NE 30D 150 hydrophobic polymer
8. Eudragit L30D . 100 hydrophobic polymer
9 Dibutyl sebecate 75 plasticizer
10. HPMC E4M 10 hydrophillic polymer
11. Magnesium Stearate 6.8 lubricant
Sorbitol Instant P300 and sodium late are combined to
starch glycol form a micro-
osmotic core.
PVP and verapamil
hydrochloride
are processed
together to yield
a
- solut ion in water. This drug system to the micro-osmotic
is spray coated on core. The
drug micro-osmotic cores are divided One portion of the drug
in two portions. system
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WO 99/63971 PCT/US99/13223
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micro-osmotic cores as manufactured above are blended with Sorbitol Instant
P300,
HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit
NE
30D (polymethacrylate copolymer dispersion) and triacetin, dried, and
delumped. One
portion of the drug system micro-osmotic cores as manufactured above are
blended with
Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating
solvent
composed of Eudragit L 30D (polymethacrylate copolymer dispersion) and
triacetin,
dried, and delumped. Material obtained in steps c and d are combined, blended
with
magnesium stearate. Controlled Release Tablets are compressed with the above
formulation. These tablets are coated with a semi-permeable polymer coating
system
composed of Eudragit NE 30D (polymethacrylate copolymer dispersion), HPMC E4M,
and triacetin.
Example 16: Capsules
containing Verapamil
hydrochloride.
Ingredients: Quantities (mglTab):Application:
1. Sorbitol Instant 220 osmotic agent
P300
2. Sodium starch glycollate40 swelling agent
3. Verapamil hydrochloride240 active
4, pZrp 6 excipient, binder
5. HPMC K100 Grade 300 hydrophillic polymer
6. Sorbitol Instant 50 hydration enhancer
P300
7. Eudragit NE 30D 100 hydrophobic polymer
8. Eudragit L30D 150 hydrophobic polymer
9. Dibutyl sebecate 75 plasticizer
10. Talc q.s. anti-caking agent
Sorbitol Instant P300 and sodium starch glycollate are processed together into
a
micro-osmotic core. PVP and verapamil hydrochloride are processed together to
yield a
solution in water. This drug system is spray coated onto the micro-osmotic
core. The
drug micro-osmotic cores are divided into two portions. One portion of the
drug system
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WO 99/63971 PCT/US99/13223
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micro-osmotic cores as manufactured above are blended with Sorbitol Instant
P300,
HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit
NE
' 30D (polymethacrylate copolymer dispersion) and triacetin, dried, and
delumped. These
granules are then coated with Eudragit L30D (polymethacrylate copolymer)
system
plasticized with dibutyl sebecate. One portion of the drug system micro-
osmotic cores as
manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade,
pelletized and granulated with a granulating solvent composed of Eudragit L
30D
(poIymethacrylate copolymer dispersion) and triacetin, dried, and delumped.
Material
obtained in steps c and d are combined, blended with talc and encapsulated
into capsules.
For examples 17-23 below, the following Felodipine Matrix component was
employed:
Felodipine USP 1.5 g
Gelucire 50/I3 1.5 g
Pluronic F 68 1.5 g
Sorbitol Instant P300 4.Og
The Gelucire and Pluronic were melted together. Felodipine was dissolved in
the
mixture, and the solution was added to Sorbitol Instant P300 while stirring.
The mixture
was mixed well and allowed to congeal. The congealed mixture was then passed
through
a ~ 20 mesh.
Example 17: In vitro release profile of felodipine tablets having a micro-
osmotic
core.
Excipients mg/tablet Supplier
HPMC E4M 112.5 Dow Chemical
Sorbitol P300 66 EMI
Avicel PH200 209.48 FMC
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WO 99/63971 PCT/US99/13223
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Felodipine Matrix 60.98 EMI
Pruv 1 Mendell
The HPMC, SorbitoI Instant, Avicel and the Felodipine Matrix were combined.
Pruv was added to the mixture and the mixture was mixed well. Samples of the
mixture (450 mg) were compressed into a tablet using Carver Press, with
compression
at 2 Ton. Each tablet was placed in a basket and the in vitro release profile
was
measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized water,
with
paddle agitation at SO rpm. Samples of the solution were taken at different
time points
and the absorbence at 362 nm was measured. The results of the measurements are
presented in the tables below and in Figure 1.
Time (h) t'~' % release s.d.
0 0 0
2 1.41421356 20.43 3.07
4 2 38.56 3.24
6 2.44948974 55.3 3.03
8 2.82842712 70.51 4.22
10 3.16227766 86.79 6.54
12 3.4641 O 162 95.24 1.4
According to the Higuchi Equation: %=Kt"~ + constant:
Tablet r slope intercept
felodipine 0.9739667 28.60726 -10.1986
According to the Zero Order Release:
SU8ST1TUTE SHEET (RULE 26)
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WO 99/63971 PCT/US99/13223
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Tablet r slope intercept
felodipine 0.9952701 8.042679 4.148214
Example 18: In vitro release profile of felodipine tablets having a micro-
osmotic core.
S Excipients mg/tablet Supplier
HPMC E4M Premium I 12.5 Dow Chemical
CR
Sorbitol P300 67.5 EMI
Avicel PH200 212.3 FMC
Felodipine Matrix 56.7 EMI
Pruv 1 Mendell
The procedures were the same as described for Example 17 above. The results of
the
measurements are presented in the tables below and in Figure 2.
Time (h) t'n 7-8 KP s.d. 6-7 KP s.d.
release % released
0 0 0 0 0 0
1 ~ 2 1.41 66.59 13.5 59.88 5.33
4 2 88.9 8.13 85.88 2.27
6 2.45 95.87 2.88 99.47 2.57
8 2.83 97.79 3.64 102.06 3.38
10 3.I6 97.46 3.08 101.72 3.42
12 3.46
According to the Higuchi Equation: %=Kt's'- + constant:
SUBSTITUTE SHEET (RULE 26)
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WO 99/63971 PCT/US99/13223
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Tablet r slope intercept
7-8 KP 0.98997 40.6174942 3.335371
6-7 KP 0.99881 41.2926417 0.81378
According to the Zero Order Release:
Tablet r slope intercept
7-8 KP 0.91526 15.496 16.352
6-7 KP 0.95079 16.2205 12.646
Example 19: In vitro release profile of felodipine tablets.
Excipients mg/tablet Supplier
E4M & K100M formulation:
HPMC E4M 106.88 Dow Chemical
HPMC K 1 OOM 5.62 Dow Chemical
Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
I S Felodipine Matrix30.36 EMI
Pruv .99 Mendell
E4M formulation:
HPMC E4M 112.5 Dow Chemical
Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
Felodipine Matrix30.36 EMI
Pruv .99 Mendell
SUBSTITUTE SHEET (RULE 26)
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WO 99/63971 PCT/US991i3223
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The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component
were combined. Pruv was added to the mixture and the mixture was mixed well.
' Samples of the mixture (445 mg) were compressed into tablets using a Carver
Press, with
compression at 2 Ton. Each tablet was placed in a basket and the in vitro
release profile
was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized
water, with
paddle agitation at 50 lpm. Samples of the solution were taken at different
time points
and the absorbence at 362 nm was measured. The results of the measurements are
presented in the tables below and in Figure 3.
Time (h) t'n 95% E4M K100 M 100% E4M
&
released s.d % released s.d.
0 0 0 0 0 0
2 1.41 14.63 2.13 15.99 6.15
4 2 41.5 3.86 42.52 7.24
6 2.45 63.26 6.21 64.29 5.4
g 2.83 75.85 6.79 78.23 5.23
IO 3.16 90.14 6.24 88.78 4.66
12 3.46 96.6 6.56 95.92 3.06
According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept
E4M & K100M 0.95949 29.55133836 -10.80056
E4M 0.96362 29.5771156 -10.11314
According to the Zero Order Release:
Tablet r slope intercept
E4M & K100M 0.99329 10.1065 -1.018
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WO 99/63971 PCT/US99/13223
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I E4M I 0.99509 ~ 10.238 I -0.746
Example 20: In vitro release profile of felodipine tablets. '
Excipients mg/tablet Supplier
HPMC E4M 101.25 Dow Chemical
S HPMC K100M 11.25 Dow Chemical
Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
Felodipine Matrix30.36 EMI
Pruv .99 Mendell
The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component
were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (445 mg) were compressed into tablets using a Carver
Press, with
compression at 2 Ton. Each tablet was placed in a basket and the in vitro
release profile
was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized
water, with
paddle agitation at 50 rpm. Samples of the solution were taken at different
time points
and the absorbence at 362 nm was measured. The results of the measurements are
presented in the tables below and in Figure 4.
Time (h) t'n HydroSolve s.d.
release
p 0 0
2 1.41 19.6 3.54
4 2 36.96 2.46
6 2.45 54.39 0
8 2.83 68.86 0.62
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WO 99/63971 PCT/US99/13223
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3.16 79.83 3.73
12 3.46 89.04 10.54
According to the Higuchi Equation: %=Kt'a + constant:
Tablet r slope intercept
5 felodipine 0.977973256626.8444051 -8.90112
According to the Zero Order Release:
Tablet r slope intercept tg
felodipine 0.9922566 7.49071429 4.8671429 11.3651187
Example 21: In vitro release profile of felodipine tablets.
10 Excipients mg/tablet Supplier
K100M formulation:
HPMC K100M 50.75 Dow Chemical
Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv .45 Mendell
E4M & K100M formulation:
HPMC E4M 40.6 Dow Chemical
HPMC K100M 10.15 Dow Chemical
Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv .45 Mendell
CA 02301042 2000-02-10
1v0 99/63971 PCT/US99/13223
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The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component
were combined. Pruv was added to the mixture and the mixture was mixed well. '
Samples of the mixture (203 mg) were compressed into tablets using a Carver
Press, with
compression at 2 Ton. Each tablet was placed in a basket and the in vitro
release profile
S was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized
water, with
paddle agitation at 50 rpm. Samples of the solution were taken at different
time points
and the absorbence at 362 nm was measured. The results of the measurements are
presented in the tables below and in Figure S.
Time (h) t'~ K100M E4M & K100M
release s.d % released s.d.
0 0 0 0 0 0
2 1.41421 15.82 2.59 18.64 2.94
4 2 34.46 2.59 46.89 7.64
6 2.44949 57.63 10.31 71.75 5.45
8 2.82843 72.32 9.79 86.44 7.38
1 S 10 3.16228 79.82 10.66 89.83 11.11
According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept
KIOOM 0.9598 26.6965209 -9.402476
E4M & K100M I 0.9655 I 31.1539762 I -9.293658
According to the Zero Order Release:
Tablet r slope intercept
K100M 0/9977 9.3225 -1.244 '
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WO 99/63971 PCT/US99113223
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~ E4M & K100M ~ 0.9953 ~ 11.2995 ~ -0.454
Example 22: In vitro release profile of tablets made from hydrosolve.
Formula I (10% Sorbitol)
Excipients mg/tablet Supplier
HPMC E4M 50.75 Dow Chemical
Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv 0.45 Mendell
The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component
were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (203 mg) were compressed into tablets using a Carver
Press, with
compression at 2 Ton. Each tablet was placed in a basket and the in vitro
release profile
was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized
water, with
paddle agitation at 50 rpm. Samples of the solution were taken at different
time points
and the absorbence at 362 nm was measured. The results of the measurements are
presented in the tables below and in Figure 6.
Time (h) t'n HydroSolve s.d.
release
0 0 0 0
2 1.414213562 53.41 3.89
4 2 85.31 6.06
6 2.449489743 98.33 1.76
g 2.828427125 101.75 1.76
' 9 3 101.75 1.76
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WO 99/63971 PCT/US99/13223
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I 10 I 3.15227766 I I I
According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept .
Felodipine 0.9907336 38.00593 1.6895071
According to the Zero Order Release:
Tablet r slope intercept
Felodipine 0.9261162 12.421 18.076
Example 23: In vitro release profile of felodipine tablets.
Excipients mg/tablet Supplier
HPMC E4M 62.19 Dow Chemical
Sorbitol P300 30.45 EMI
Avicel PH200 94.73 FMC
Felodipine Matrix15.18 EMI
Pruv 0.45 Mendell
The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component
were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (203 mg) were compressed into tablets using a Carver
Press, with
compression at 2 Ton. Each tablet was placed in a basket and the in vitro
release profile
was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized
water, with
paddle agitation at 50 rpm. Samples of the solution were taken at different
time points
and the absorbence at 362 nm was measured. The results of the measurements are
presented in the tables below and in Figure 7.
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WO 99/63971 PCT/US99/13223
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Time (h) t'n HydroSolve
release
0 0 0
2 I .41421356 20.27
4 2 48.65
6 2.4494897 67.12
According to the Higuchi Equation: %=Kt"~ + constant:
Tablet r slope intercept
Felodipine 0.9723567 31.17882739 -9.19942
According to the Zero Order Release:
Tablet r slope intercept
Felodipine 0.9897404 9.729285714 3.755238
The preceding examples can be repeated with similar success by substituting
the
generically or specifically described reactants and/or operating conditions of
this
invention for those used in the preceding examples.
Without further elaboration, it is believed that one skilled in the art can,
using the
preceding description, utilize the present invention to its fullest extent.
The preceding
preferred specific embodiments are, therefore, to be construed as merely
illustrative, and
not limitative of the remainder of the disclosure in any way whatsoever.
The entire disclosure of all patent applications, patents, and publications
cited
herein are hereby incorporated by reference.
From the foregoing description, one skilled in the art can easily ascertain
the
essential characteristics of this invention and, without departing from the
spirit and scope
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WO 99/63971 PCT/iJS99/13223
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thereof, can make various changes and modifications of the invention to adapt
it to
various uses and conditions.
