FIELD OF THE INVENTION:
The present invention relates to a modified release composition of at least one form of
venlafaxine, which is an upgraded ingestion deferred controlled discharge structure for oral
organization reasonable for once everyday dosing. The structure involves a center
containing something like one type of venlafaxine chose from the gathering comprising of
venlafaxine, a functioning metabolite of venlafaxine, a chemically satisfactory salt of
venlafaxine, a chemically acceptable salt of a functioning metabolite of v·enlafaxine, and
mixes thereof, and a chemically acceptable excipient.
BACKGROUND OF THE INVENTION:
The present invention pertains to procedures for the preparation of modified release
formulations for oral administration of at .least one form of venlafaxine,- as well as to their
use in medicine. The modified release composition is specifically related to a delayed
controlled release composition of venlafaxine in at least one form with ·increased
/
absorption.
The structure further includes a changed delivery covering. which considerably encompasses
the center. The pieces of the creation give improved ingestion deferred controlled arrival of
the no less than one type of venlafaxine to such an extent that the consolidated
mathematical mean proportion of the sythesis of the innovation to the reference item for
the AU CO-t or the Cmax for venlafaxine and its dynamic metabolite 0-desmethylvenlafaxine
is more prominent than 2 after first organization of the arrangement deprived or fasting
conditions.
For many drugs, the optimum dosage regimen is one that promptly achieves a tolerable
therapeutic drug concentration at the site(s) of action and then maintains that
concentration over the course of the treatment. Therapeutic "steady-state" plasma
concentrations of a medication can be quickly reached and maintained by the repeated
administration of standard peroral dosage forms, provided the dose size and frequency of
administration are appropriate. With standard peroral dose forms, there are a few possible
drawbacks, though. Pharmaceutical researchers are now thinking about delivering
therapeutically effective compounds in "extended-release" formulations due to these
restrictions.
2
The conventional favoured form of drug delivery is oral consumption, which offers a
practical way. to efficiently produce both local and systemic effects. The target site should
receive a consistent, measured, and repeatable amount of medication over an extended
period of time via an optimal oral drug delivery system. In order" to maintain plasma
concentrations within a therapeutic range for an extended period of time after absorption,
extended-release (ER) delivery systems provide a uniform concentration/amount of the
drug at the absorption site. This can minimise side effects and also reduce the frequency of
administration. Slow medication release in ER dosage forms keeps plasma concentrations at
therapeutic levels for a longer length of time.
The cyclical fluctuations in plasma drug concentration that occur following administration of
a traditional .delivery system have led to the· development of numerous drug delivery
methods. These systems have been referred to by a number of names, including modified
release, prolonged release, sustained release, extended release, and delayed release. It's
important to note that the USP regards the terms extended-release, sustained release,
prolonged release, and controlled release as being equivalent.
The cyclical fluctuations in plasma drug concentration that occur following administration of
a traditional delivery system have led to the development of numerous drug delivery
methods. These systems have been referred to by a number of names, including modified
release, prolonged release, sustained release, extended release, and delayed release: It's
important to. note that the USP regards the terms extended-release, sustained release,
prolonged release, and controlled release as being equivalent.
Summary of the invention:
The present invention relates to a modified release composition of a wide variety of
modified release formulation of at least one type of venlafaxine
In the present invention, the modified release composition of the at least one form of
venlafaxine is a pharmaceutical composition for oral administration suitable for once-daily
dosing that includes the following ingredients: a) a core consisting of at least one form of
venlafaxine chosen from the group consisting of venlafaxine, a pharmaceutically acceptable
3
salt of venlafaxine, an active metabolite of venlafaxine, a pharmaceutically acceptable salt
and more, b) a changed delivery covering which considerably encompasses said center,
wherein said piece gives improved retention postponed controlled arrival of said something
like one type of venlafaxine. with the end goal that the consolidated mathematical mean
proportion of the sythesis of the creation to the reference item for the AU CO-t or the Cmax
for venlafaxine or its dynamic metabolite 0-desmethylvenlafaxine is more prominent than 1
after first organization starved or fasting conditions.
The term "geometric mean ratio" as used herein refers to the ratio of the invention's
composition's geometric mean to the reference product's geometric mean for a particular
pharmacokinetic parameter. For instance, the "geometric mean ratio" for the AUCO-t for
venlafaxine is calculated by dividing the geometric mean of the invention's composition's
AUCO-t for venlafaxine by the reference product's 'AUCO-t for venlafaxine. Hence, if the
mathematical mean for the AU CO-t for venlafaxine of the arrangement of the development
is X and the mathematical mean for the AUCO-t for venlafaxine for reference item is Y, then
the mathematical mean proportion for the AUCO-t for venlafaxine is X/Y. Essentially, if the
mathematical mean for the AUCO-t for 0-desmethylvenlafaxine of the sythesis of the
creation is An and the mathematical mean for the AU CO-t for 0-desmethylvenlafaxine of the
reference item is B, th'en the mathematical mean proportion for the AUCO-t for 0-
desmethylvenlafaxine is A/B. As utilized thus, the "joined mathematital mean proportion"
signifies the mathematical mean proportion of venlafaxine for a specific pharmacokinetic
boundary in addition to the mathematical mean proportion of 0-desmethylvenlafaxine for
the equivalent pharmacokinetic boundary. To utilize the above model, the joined
mathematical mean proportion for the AU CO-t is subsequently [(X/Y)+(A/B)].
In this document, the term "first administration" refers to the first single dose of the
invention's composition given to a patient or the first dose given to a patient after a suitable
washout period.
The enhanced absorption delayed controlled release pharmaceutical composition for oral
administration that is suitable for once-daily dosing includes the following components in
another embodiment of the invention: a) a center involving no less than one type of
venlafaxine chose from the gathering comprising of venlafaxine, a chemically OK salt of
4
venlafaxine, a functioning metabolite of venlafaxine, a chemically OK salt of a functioning
metabolite of venlafaxine, and blends thereof, and chemically OK excipient; furthermore, b)
a covering considerably encompassing said center, said covering involving a water-insoluble
water-penetrable film-framing polymer, a water-solvent polymer or substance, and a
plasticizer, wherein said piece gives upgraded retention deferred controlled arrival of said
something like one type of venlafaxine with the end goal that the joined mathematical
mean proportion of the structure of the development to the reference item for the AU CO-t
or the Cmax ·tor venlafaxine or its dynamic metabolite 0-desmethylvenlafaxine is more
noteworthy than 1 after first. organization deprived or fasting conditions.
Another version of the enhanced absorption delayed controlled release pharmaceutical
composition for oral administration suitable for once daily dosing includes: a) a core
consisting of at h~ast one form of venlafaxine chosen from the list of venlafaxine, a
pharmaceutically acceptable salt of venlafaxine, an active metabolite of venlafaxine, a
pharmaceutically acceptable salt of an active metabolite of venlafaxine, and combinations
thereof; and b) a pharmaceutically acceptable and b) a coating largely enclosing said core,
said coating made up of a water-insoluble water-permeable film-forming polymer, a watersoluble
polymer or substance, and a plasticizer, wherein said composition exhibits an in
vitro dissolution profile when tested using the USP Type I apparatus method at 75 rpm in
1000 ml of phosphate buffer pH 6.8 at 37' C. as shown by the equation:
y=lOO-lOO*e (~a•x b)
where,
0
•
•
•
•
•
y=% dissolution,
x=sampling time,
a;,scale parameter which ranges from about 0.07 to about 0.0004,
b=shape parameter which ranges from about 1.48 to about 3.02, and
lOO=the cumulative
percentage of the at least one form of venlafaxine released at time
infinity
Another version of the enhanced absorption delayed controlled release pharmaceutical
composition for oral administration suitable for once daily dosing includes: a) a core
consisting of at least one form of venlafaxine chosen from the list of venlafaxine, a
5
pharmaceutically acceptable salt of venlafaxirie, an active metabolite of venlafaxine, a
pharmaceutically acceptable salt of an active metabolite of venlafaxine, and combinations
thereof; and b) a pharmaceutically acceptable and b) a coating largely enclosing said core,
said coating made up of a water-insoluble water-permeable film-forming polymer, a watersoluble
polymer or substance, and a plasticizer, wherein said composition exhibits an in
. vitro dissolution profile when tested using the USP Type I apparatus method at 75 rpm in
1000 ml of phosphate buffer pH 6.8 at 3r C. as shown by the equation for the first dosage
of venlafaxine while the patient was fed or fasting, the AU CO-t and/or Cmax was larger than
2.
The enhanced absorption delayed controlled release pharmaceutical composition for oral
administration suitable for once-daily dosing in another embodiment of the invention
consists of: a) a center involving no less than one type of venlafaxine chose from the
gathering comprising of venlafaxine, a chemically OK salt of venlafaxine, a functioning
metabolite of venlafaxine, a chemically OK salt of a functioning metabolite of venlafaxine,
and blends thereof, and chemically OK excipient; b) a coating that covers most of the core
and is made of a water-insoluble, water-permeable film-forming polymer, a water-soluble
polymer, or substance, and a plasticizer. The composition of the invention provides
enhanced absorption, delayed controlled release of at least one form of venlafaxine, and
the geometric mean ratio of the composition to the reference product for the AUCO-t
and/or the Cmax for 0-desmethylvenlafaxine is greater than 2
When the composition of the invention is administered under fed conditions, the combined
geometric mean ratio for the AUCO-t is approximately 2.32 in one embodiment of the
invention.
When the composition of the invention is administered under fasting conditions, the
combined geometric mean ratio for the AUCO-t is approximately 2.33 in one embodiment of
. the invention.
In one exemplification .of the development, the joined mathematical mean proportion for
the Cmax is around 2.65 when the sythesis is directed starved conditions.
6
When the composition is administered under fasting conditions, the combined geometric
mean ratio for the Cmax is approximately 2.38 in one embodiment of the invention.
When administered under fed conditions, the composition of the invention has a Tmax that
is approximately 5 hours later than that of the reference product for venlafaxine in one
embodiment of the invention.
In one exemplification of the development, the Tmax of the piece of the creation contrasted
with the reference item for 0-desmethylvenlafaxine is deferred by around 2 hours when the
sythesis is managed deprived conditions.
When the composition is administered under fasting conditions, the Tmax of the invention's
composition is delayed by approximately two hours compared to the reference product for
venlafaxine or 0-desmethylvenlafaxine in one embodiment of the invention.
The Tmax of venlafaxine or 0-desmethylvenlafaxine is greater than 8 hours after the first
administration of the composition in the fed or fasted state in one embodiment of the
invention.
In one epitome of the creation, the Tmax for venlafaxine is at around 11 hours after first
organization of the piece in the fed state.
0-desmethylvenlafaxine's Tmax is approximately 12 hours after the first fed-state
administration in one embodiment of the invention.
In one epitome ·of the .creation, the Tmax for venlafaxine is at around 10 hours after first
organization of the arrangement in the abstained state.
In one exemplification of the development, the Tmax for 0-desmethylvenlafaxine is at
around 14 hours after first organization of the creation in the abstained state.
7
After first administering the composition in the fed state, the composition in one
embodiment of the invention offers a Cmax for venlafaxine or 0-desmethylvenlafaxine
more than 150 ng/ml.
After first administering the composition in the fed state, the composition in one
embodiment of the invention offers a Cmax of about 160 ng/ml for venlafaxine.
After first administering the composition in the fed state, the composition delivers a Cmax
of approximately 211 ng/ml for 0-desmethylvenlafaxine in one embodiment of the
invention.
Venlafaxine hydrochloride, venlafaxine besylate, venlafaxin maleate, and venlafaxin
fumarate are among the venlafaxine salts that are pharmaceutically acceptable in one
embodiment of the invention.
The hydrochloride salt of venlafaxine is the pharmaceutically approved salt of venlafaxine in
one embodiment of the invention.
[0046]
0-desmethylvenlafaxine is one example of the invention's active metabolite of venlafaxine.
0-desmethylvenlafaxine succinate is a pharmaceutically acceptable salt of an active
metabolite of venlafaxine in one embodiment of the invention.
The hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene ·.oxide,
polyvinylpyrrolidone, carbomers, carragheen, polyvinylalcohol, and mixtures thereof are all
options for the at least one gelling agent in one version of the invention. At least one gelling
agent should make up between 10 and 80 percent, preferably between 10 and 40 percent,
and most preferably around 2.1 percent by weight of the core dry weight. Preferably, the
mixture of at least two gelling agents-hydroxypropylmethylcellulose (13 percent) and
polyvinylpyrrolidone (8%)-makes up the at least one gelling agent.
In one exemplification of the development, the center further contains something like one
filler chose from the gathering comprising of lactose monohydrate, anhydrous lactose,
mannitol, sorbitol, microcrystalline cellulose, dibasic calcium, calcium sulfate and
8
combinations thereof. Up to about 75% of the core's dry weight is made up of at least one
filler. Ideally, the filler is lactose monohydrate, explicitly Lactose # 315 Splash Dried, and
contains by weight around 23% by weight of the center dry weight.
The core of one version of the invention also includes at least one lubricant from the
categories of magnesium stearate, talc, stearic acid, sodium stearyl fumarate, calcium
stearate, vegetable oil, silica gel, colloidal silicon dioxide, and Compritol 888 ATO, as well as
combinations of these ingredients. From about 0.02 to about 5%, preferably from about 0.5
to about 2%, and even more preferably from about 0.5 to about 1% by weight, the at least
one lubricant accounts for the core dry weight. The filler, which should ideally be
magnesium stearate, accounts for approximately 0.65 percent of the core's dry weight.
Using the USP type I method at 75 rpm in 1000 ml phosphate buffer pH 6.8 at 37" C, the
modified release coating for the enhanced absorption delayed controlled release of at least
one form of venlafaxine provides an in vitro release profile that is characterized by the
equation:
• y=100-100*e <-•·· ''
where,
0
• y'=% dissolution,
• x=sampling time,
• a=scale parameter which ranges from about 0.07 to about 0.0004,
· • b=shape parameter which ranges from about 1.48 to about 3.02, and
• 100=the cumulative percentage of the active released at time infinity.
Preferably, the modified release coat comprises by weight based on
the coating weight, about 20 to about 85% of at least one waterinsoluble
water-permeable film-forming polymer, about 10 to about
75% of at least one water-soluble polymer or substance, and about 3
to about 40% of at least one plasticizer. Preferably,
the at least one form of venlafaxine is venlafaxine hydrochloride.
The at least one water-insoluble, water-permeable film-forming polymer is chosen from
among ethylcellulose, cellulose acetate, methacrylic acid derivatives, Surelease'", Acryi-EZE'",
and combinations thereof in one embodiment of the invention. Ethyl cellulose should make
up at least one water-insoluble, water-permeable film-forming polymer, and its weight
9
should be between SS and 62% of the coating's weight. Ethylcellulose should ideally make
up approximately 55% of the coating's weight by weight.
In one version of the invention, at least one water-soluble polymer is chosen from the
following: polyvinylpyrrolidone; polyethyleneglycol; hydroxypropylmethylcellulose;
hydrated colloidal silica; sucrose; mannitol; and combinations of these substances. Ideally,
polyvinylpyrrolidone is the at least one water-soluble polymer, making up between 26 and
32 percent of the coating's weight, depending on the coating's weight. Preferably, about
32% of the coating's weight is made up of polyvinylpyrrolidone.
Citrate esters, dibutyl sebacate, dibutyl pthalate, triacetin, castor oil, polyalkyleneglycol,
fatty acids, and combinations thereof are among the plasticizers used in one version of the
invention. Stearic acid is preferred as the at least one plasticizer, accounting for
approximately 13 to 14% of the coating's weight by weight. Most ideally, the stearic
-corrosive contains around 13.5% by weight of the covering weight.
The weight gain caused by applying the delayed-and extended release coating to the core in
one version of the invention ranges from about 2 to about 50 percent, preferably from
about 2 to about 20 percent, more preferably from about 7.5 to about 10 percent, and most
preferably from about 8 percent of the core's dry weight.
The water-insoluble, water-permeable film-forming polymer's weight proportions in one
version of the invention are as follows: water-solvent polymer: Plasticizer should be around
55-62:26-32:13:14, most preferably around 55:32:13.5, and preferably around 50-85:10-
40:5-20.
When tested in vitro using the USP type I method at 75 rpm in 1000 ml of phosphate buffer
at pH 6.8 at 37" C, the oral dosage form in another embodiment of the invention releases
venlafaxine hydrochloride in a manner that is characterized by the equation:
, y=100-100*e ,_,., ''
where,
0
• y=% dissolution,
• x=sampling time,
• a=scale parameter which ranges from about 0.07 to about 0.0004,
• b=shape parameter which ranges from about 1.48 to about 3.02, and
10
lOO=the cumulative
released at time infinity.
percentage of venlafaxine hydrochloride
When tested in vitro using the USP type I method at 75 rpm in 1000 ml of phosphate buffer
at pH 6.8 at 37' C, the oral dosage form provides a dissolution rate of between 0% and 6.8%
venlafaxine hydrochloride after one hour, 0.5% to 18% after two hours, 3% to 42% after four
hours, 9% to 63% after six hours, 19% to 78% after eight hours, 34% to 94% after ten hours,
5.
In a different version of the invention, when the oral dosage form is given to a patient who
needs it, the incidence of adverse events that aren't caused by food is the same or lower
than that of the reference product.
Objectives of the present invention:
It is a primary object of the present invention to modified release venlafaxine, It is used to
treat low mood (depression). It is used to treat anxiety. It is used to treat panic attacks. It
may be given to you for other reasons
It is the further objective of the present invention to provide the composition of venlafaxine,
each tablet contains either 37.5 mg or 75 mg venlafaxine as venlafaxine hydrochloride. The
other ingredients are: lactose monohydrate, microcrystalline cellulose, sodium starch
glycolate, povidone, magnesium stearate, ferric oxide yellow (E-172), ferric oxiCie red (E-
172)·and ferric oxide black (E-172).
It is the further objective of the present invention to method of preparing the controlled
release formulation is another objective of the present invention.
It is the further objective of the invention to provide a method of invention also· aims to
provide a Venlafaxine is extensively metabolised, primarily to the active metabolite, 0-
desmethylvenlafaxine {ODV) .. Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2
hours and 11±2 hours, respectively.
Description of the invention:·
The present disclosure is subject to modifications Venlafaxine is an antidepressant drug that
belongs to the SNRI (serotonin-norepinephrine reuptake inhibitor) class. It is used to treat
major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety
disorder. It may also be used to treat chronic pain. It is taken orally. It is also available as the
salt venlafaxine besylate in an
II
The particular embodiments that are presented here are only meant to serve as examples
and do not limit the scope of the present disclosure.
"Normal aftereffects incorporate loss of hunger, dogging, dry mouth, discombobulation,
perspiring, a sleeping disorder, tiredness and sexual problems. Extreme secondary effects
incorporate an expanded gamble of self destruction, madness, and serotonin syndrome.
Energizer withdrawal condition might happen if stopped. There are worries that utilization
during the later piece of pregnancy can hurt the baby. How it functions isn't completely
clear, yet it is by all accounts connected with the potentiation of the movement of certain
synapses in the brain.
In the United States, venlafaxlne was given the go-ahead tor medicinal use in 1993.1t is
accessible as a generic drug. With more than 15 million prescriptions written in 2020, it was
the 43rd most often prescribed drug in the US.
The dynamic substance is venlafaxine. Venlafaxine hydrochloride, 37.5 mg or 75 mg, is
present in each tablet. Different fixings are: microcrystalline cellulose, lactose monohydrate,
sodium starch glycolate, povidone, magnesium stearate, ferric oxide yellow (E-172), red (E-
172), and black (E-172).
The main conditions that are treated with venlafaxine are vasomotor symptoms, social
phobia, panic disorder, generalised anxiety disorder, and depression.
Off-label uses of venlafaxine include migraine prophylaxis and the treatment of diabetic
neuropathy. It might reduce pain via having an impact on the opioid receptor. Additionally,
it has been discovered to lessen the severity of "hot flashes" in men and women going
through menopause who are receiving hormonal therapy for prostate cancer.
Venlafaxine is also used as a medication to lessen episodes of cataplexy, a type of muscle
weakness, in. individuals with the sleep condition narcolepsy since it acts on both the
serotoninergic and adrenergic systems. Three double-blind studies and a few open-label
studies have revealed that venlafaxine is effective in treating attention deficit hyperactivity
disorder.
Depression
12
Venlafaxine, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, and
vortioxetine were found to be more effective than other antidepressants in a comparative
meta-analysis of 21 main antidepressants, even though the quality of several comparisons
was rated as low or very low.
The effectiveness of venlafaxine was comparable to that of the atypical antidepressant
bupropion, although venlafaxine had a lower remission rate.[23) Patients who did not
respond to an SSRI were shifted to either venlafaxine or another SSRI (citalopram) in a
double-blind research; the results showed equivalent improvement in both groups.
Its effectiveness for use by youngsters has not been proven by studies. Venlafaxine raises
the likelihood of suicidal ideas or actions in children and adolescents with depression.
According to studies, venlafaxine's delayed release type is preferable to the quick release
variety.
According to a meta-analysis, the effectiveness of venlafaxine is not related to the severity
of depression at baseline.
Venlafaxine (brand name Effexor) is an antidepressant used in the treatment of major
depressive disorder, anxiety, and panic disorders. Venlafaxine belongs to the drug class of
serotonin and norepinephrine reuptake inhibitors (SNRis), as does its major metabolite,
desvenlafaxine .(brand name Pristiq).
The recommended starting dose for venlafaxine is 75 mg/day, divided into 2 or 3 doses.
Depending on tolerability and clinical response, the dose may be increased to 150 mg/day,
and if needed, further increased. up to 225 mg/day. Only the more severely depressed
individuals may respond to higher doses, up to a maximum of 375 mg/day.
Venlafaxine is metabolized into its major active .metabolite, 0-desmethylvenlafaxine (ODV),
primarily by the CYP2D9 enzyme. As such, individuals that have high plasma concentrations
of venlafaxine and low plasma concentrations of ODV when taking venlafaxine, indicates
they have reduced or absent CYP206 activity. This can be caused by concomitant use of
medications that inhibit the CYP206 enzyme or by germline genetic variation in
the CYP206 gene. Individuals who have· genetic variants associated with no enzyme activity
are called "CYP2D6 poor metabolizers" and account for approximately 7% of Caucasians.
Drug: Venlafaxine
Venlafaxine is an antidepressant used in the treatment of major depressive disorder,
generalized anxiety disorder, social anxiety disorder, and panic disorder. An off-label use of
venlafaxine is in the management of post-traumatic stress disorder.
13
Venlafaxine is thought to exert its antidepressant effect by blocking the transporter
reuptake proteins for key neurotransmitters affecting mood, thereby leaving more active
neurotransmitters in the synapse. This is known as the "potentiation of neurotransmission".
Venlafaxine belongs to the drug class of serotonin-norepinephrine reuptake
inhibitors (SNRis). Other drugs with SNRI activity include atomoxetine (used in the
treatment ot' ADHD) and tramadol (an analgesic). However, because venlafaxine also weakly
inhibits dopamine reuptake, it is also referred to as a serotonin-norepinephrine-dopamine
reuptake inhibitor (SNDRI).
The· toxicity of venlafaxine appears to be higher than for other drugs of the same class. Side
effects include an increase in anxiety, insomnia, and nervousness; the precipitation of mania
or hypomania in individuals with bipolar disorder; as well as weight loss, reduced appetite,
hyponatremia, seizures, cardiac conduction abnormalities, and an increased risk of bleeding ·
events.
There is also a risk of discontinuation syndrome, which may occur if Venlafaxine therapy is
stopped abruptly or if the dose is reduced. Symptoms include agitation, anorexia, anxiety,
and confusion. A gradual reduction in the dose of venlafaxine is recommended, whenever ·
possible.
Venlafaxine is metabolized in the liver to its major active metabolite, ODV. Venlafaxine and
ODV share similar activity, and ODV is also an FDA-licensed antidepressant (desvenlafaxine).
We claim:
1. An enhanced absorption delayed controlled release pharmaceutical composition for
oral administration suitable for once-daily dosing contains: a) a core consisting of at
least one form of venlafaxine chosen from the group consisting of venlafaxine, a
pharmaceutically acceptable salt of venlafaxine, an· active metabolite of venlafaxine,
a pharmaceutically acceptable salt of an active metabolite of venlafaxine, and
combinations thereof; and b) a core The composition of the invention provides
enhanced absorption delayed controlled release of said at least one form of
venlafaxine such that the combined geometric mean ratio of the composition of the
invention to the reference product for the AUCO-t for venlafaxine and its active
metabolite 0-d is greater than one. b) a coating substantially surrounding said core,
said coating consisting of a water-insoluble water-permeable film-forming polymer,
a water-soluble polymer or substance, and a plasticizer, wherein said composition
offers ·enhanced absorption delayed controlled release of said at least one form of
verilafaxine such that the combined geometric mean ratio of the. composition of the
invention to the reference product for the AUCO-t for venlafaxine and its active
14
metabolite 0-desmethylvenlafaxine after first administration under fed or fasting
conditions is greater than 1.
2. The substance of claim 1, wherein the combined geom!!tric mean ratio for the AU COtis
approximately 2.32 when fed.
3. The mixtu·re of claim 1, where the combined geometric mean ratio for the AUCO-t
during fasting c1;mditions is approximately 2.33.
4. The mixture of claim 1, wherein the combined geometric mean ratio for the Cmax is
approximately 2.65 under fed circumstances.
5. The compound of claim 1 in which the combined geometric mean ratio for the Cmax
is approximately 2.38 when fasting.
6. The composition of claim 1, where.in .the Tmax of the composition for venlafaxine is
delayed by about 5 hours when compared to the reference product.