WO 2007/011619 PCT/US2006/027106
HIGHLY BIOAVAILABLE ORAL DELAYED RELEASE DOSAGE
FORMS OF O-DESMETHYLVENLAFAXINE SUCCINATE
The invention relates to an oral, highly bioavailable dosage form of O-
desmethylvenlafaxine succinate, and to its use in treating depression and reducing the
side-effects of O-desmethylvenlafaxine.
BACKGROUND OF THE APPLICATION
O-desmethylvenlafaxine (ODV), the major metabolite of venlafaxine,
selectively blocks the reuptake of serotonin and norepinephrine. Klamerus, K. J. et
al., "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine
and its Active O-Desmethyl Metabolite", J. Clin. Pharmacol. 32:716-724 (1992). O-
desmethyl-venlafaxine, chemically named l-[2-(dimethylamino)-l-(4-phenol)ethyl]-
cyclohexanol, was exemplified as a fumarate salt in U.S. Pat. No. 4,535,186.
However, the fumarate salt of O-desmethyl-venlafaxine has unsuitable
physicochemical and permeability characteristics. O-desmethyl-venlafaxine is also
exemplified as a free base in International Patent Publication No. WO 00/32555.
The succinate form of ODV has been described [US Patent 6,673,838]. The
succinate monohydrate form of ODV has been incorporated into an extended release
hydro-gel tablet, which reduces adverse effects such as nausea, vomiting, diarrhea,
and abdominal pain. Formulations describing the use of hydroxypropyl
methylcellulose (HPMC) as the hydrogel matrix have been described [WO 02/064543
A2].
However, the effects of the hydrogel formulation have been observed to be
variable when the ODV hydrogel tablet is given with food.
SUMMARY OF THE INVENTION
The present invention provides oral delayed release dosage units composed of
ODV succinate, termed herein DVS, and an enteric coat in the range of about 10 to 20
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wt% of the dosage unit. These oral delayed release dosage units enhance
bioavailability, reduce undesirable side effects, and reduce variability in plasma.
Advantageously, in one embodiment, the compositions of the invention
enhance the bioavailability of ODV succinate by deferring release of most of the
ODV succinate until such time as the formulation is in the ileum and small intestine,
while minimizing colonic release. Further, compositions described herein provide
sustained release over a period of at least 8 hours, while providing at least about 85%
total release within 12 hours of the oral dosage unit being taken orally.
These and other advantages of the invention will be readily apparent from the
following detailed description of the invention.
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 provides a chart showing the release profile of a superbioavailable 150
mg DVS oral dosage unit of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an oral, highly bioavailable, dosage unit of
DVS. These sustained release formulations lower the incidence of side effects,
including nausea, emesis, and irritable bowel syndrome. Without wishing to be
bound by theory, it is believed that these side-effects are avoided by by-passing
release in the upper GI tract and providing release in the lower GI tract. Further, use
of the superbioavailable DVS provided herein is believed to result in reduced patient
variability in plasma exposure.
Advantageously, in one embodiment, the superbioavailable DVS formulation
of the invention comprises DVS in an oral dosage unit having a delayed release of at
least about one hour and a sustained release over multiple hours to provide a total
release of greater than about 85% within about 12 to about 14 hours. In one
embodiment, the superbioavailable sustained release DVS formulation has a delayed
release of about two hours and a total release of greater than about 95% within about
12 to about 14 hours.
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In one embodiment, the DVS oral dosing units of the invention are composed,
at a minimum, of a core containing DVS, and one or more pharmaceutically
acceptable excipients. Suitably, the core contains about 40 wt% to about 60 wt%
DVS, about 45 to 55 wt%, or about 47 to 52 wt%, of the total oral dosing unit. The
core containing the DVS may be in a sustained release formulation or other suitable
cores as are described in greater detail below may be selected. In one embodiment, a
delay release coat and/or an enteric coat are provided over the core.
The delay release coat and/or an enteric coat (rate-controlling film) can be
applied to the DVS core directly, or there may be intermediate coating layers located
between the DVS core and any over coats. Optionally, a further seal or top coat may
be located outside the enteric coat.
DVS is prepared as described in US Patent 6,673,838, which is incorporated
by reference herein. In other embodiments, the DVS can range from about 20% w/w
to about 75 wt % w/w, 25 wt% to about 50 wt%, from about 30 wt % to about 45 wt
%, or from about 35 wt % to about 55 wt %, based upon 100% weight of the core.
Suitably, the DVS can range from about 10 % w/w to about 70 % w/w of the total oral
dosage unit, and preferably, about 40 to about 60 wt%, and more preferably, about 50
to about 55 wt% of the total weight of the oral dosage unit.
In one embodiment, the core contains about 25 wt% to about 30 wt %
microcrystalline cellulose. In other embodiments, the core may contain another
binder or additional binders, or further excipients such as diluents, fillers, glidants,
anti-adherents, and adjuvants to provide a total amount of excipients in the core of
about 25 wt % to about 80 wt % w/w of the core.
For example, when present, one or more binder/fillers and/or diluents can each
be present in an amount of about 15 % w/w to about 80 % w/w, or about 20% w/w to
about 70 % w/w, or about 25% w/w to about 45% w/w, or about 30% w/w to about 42
% w/w of the uncoated dosage form. The total amount of a pH adjuster in the
formulation can range from about 0.1% w/w to about 10% w/w of the core, or about
1% w/w to about 8% w/w, or about 3% w/w to about 7% w/w. However, these
percentages can be adjusted as needed or desired by one of skill in the art.
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In one embodiment, the filler/binder is water insoluble. The filler/binder may
be selected from among known fillers/binders, including, e.g., cellulose, and
povidone, among others. In one embodiment, the filler/binder is selected from among
rnicrocrystalline cellulose, crospovidone, and mixtures thereof. Other suitable
fillers/binders, including those that are water soluble or partially water soluble may be
used in combination with water insoluble fillers/binders, as needed.
Suitable pH adjusters include, e.g., sodium carbonate, sodium bicarbonate,
potassium carbonate, lithium carbonate, among others. Still other suitable
components will be readily apparent to one of skill in the art.
In one embodiment, the DVS core is provided with further layers that provide
a sustained release formulation which contains rate-controlling components.
Typically, such rate controlling components are rate controlling polymers selected
from among hydrophilic polymers and inert plasticized polymers. Suitable rate
controlling hydrophilic polymers include, without limitation, polyvinyl alcohol
(PVA), hypomellose and mixtures thereof. Examples of suitable insoluble or inert
"plastic" polymers include, without limitation, one or more polymethacrylates (i.e.,
Eudragit® polymer). Other suitable rate-controlling polymer materials include, e.g.,
hydroxyalkyl celluloses, poly(ethylene) oxides, alkyl celluloses, carboxymethyl
celluloses, hydrophilic cellulose derivatives, and polyethylene glycol.
Thus, in one embodiment, the formulation of the invention contains one or
more coatings over the DVS core. In still other embodiments, the core can contain a
non-functional seal coating (i.e., a coat which does not affect release rate) and a
functional second coating.
In one embodiment, an initial seal coat can be applied directly to the core.
Although the components of this seal coat can be modified by one of skill in the art,
the seal coat may be selected from among suitable polymers such as hydroxypropyl
methylcellulose (HPMC), ethylcellulose, polyvinyl alcohol, and combinations thereof,
optionally containing plasticizers and other desirable components. A particularly
suitable seal coat contains HPMC. For example, a suitable seal coat can be applied as
a HPMC solution at a concentration of about 3% w/w to 25% w/w, and preferably 5%
w/w to about 7.5% w/w.
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The initial seal coat can be applied on a fluid bed coater, e.g., by spraying. In
one embodiment, an Aeromatic Strea™ fluid bed apparatus is fitted with a Wurster
column and bottom spray nozzle system. Approximately 200 grams of the dried
pellet cores are charged into the unit. The Opadry® Clear seal coat is applied with an
inlet temperature of approximately 50°C to 60°C, a coating solution spray rate of 5 to
10 grams/minute, atomization pressure of 1 to 2 bar. The desired product temperature
is 35°C to 45°C, and preferably 38°C to 43°C.
Upon drying, under suitable conditions, the initial seal coat is in the range of
about 1 % w/w to about 3% w/w, or about 2% w/w, of the uncoated core. In another
embodiment, a commercially available seal coat containing HPMC, among other inert
components, is utilized. One such commercially available seal coat is Opadry® Clear
(Colorcon, Inc.).
In one embodiment, the oral dosage unit contains a further release or "delay"
coating layer. This release coating layer may be applied over an initial seal coat or
directly over a core.
In one embodiment, the release coat is a controlled release coating layer which
contains an ethylcellulose-based product. An example of one suitable ethylcellulose-
based product is an aqueous ethylcellulose dispersion (25% solids). One such product
is commercially available as Surelease® product (Colorcon, Inc.). In one
embodiment, a solution of an aqueous ethylcellulose (25% solids) dispersion of about
3% w/w to about 25% w/w, and preferably about 3% to about 7%, or about 5% w/w,
is applied to the core. In another embodiment, the controlled release coat contains
both an ethylcellulose-based product and hypomellose. Optionally, hypomellose, e.g.,
in an amount of about 5 to 15% by weight, and preferably, about 10% by weight, is
mixed with the ethylcellulose dispersion, to form the coat solution. Thus, such the
ethylcellulose may be about 85% to about 95%, by weight, or in embodiment, about
90% by weight, of the coat solution. Upon drying under suitable conditions, the total
controlled release coat is in the range of about 2% to about 5%, or about 3% to about
4% w/w of the uncoated or initially-coated core.
In one embodiment, the oral dosage unit contains an enteric coat, which can
provide an initial "delay". In certain embodiments, the enteric coat may delay release
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for as much as about 30 minutes to two hours. The enteric coat may be applied over
the controlled release coat, over an initial seal coat, or directly over a core.
The enteric coat may contain, e.g., polymethacrylates, hypomellose, and
ethylcellulose, or a combination thereof
In one embodiment, the enteric coat contains a product which is a copolymer
of methacrylic acid and methacrylates, such as the commercially available Eudragit®
L 30 K55 (Rohm GmbH & Co. KG). Suitably, this enteric coat is applied such that it
coats the core in an amount of about 10 wt % to 20 wt %, or about 12 wt % to about
17 wt %, or about 15.5 wt % to 16.5 wt % of the uncoated or initially-coated core.
In one embodiment, the enteric coat is composed of a Eudragit® L30D-55 copolymer
(Rohm GmbH & Co. KG), talc, triethyl citrate, and water. More particularly, the
enteric coating may contain about 7 wt % to about 9 wt% of a 30 wt% dispersion of
Eudragit® L 30 D55 coating; about 4 wt% to about 5 wt % /w talc, about 0.7 wt% to
about 1 wt % triethyl citrate; a pH adjuster such as sodium hydroxide and water.
The enteric coat can be applied directly to the uncoated spheroid core, i.e., the
uncoated core, or may be applied over an initial seal coat. The enteric coat, as
described above, is typically applied on a fluid bed coater. In one embodiment,
Surelease® aqueous ethylcellulose dispersion (25% solids) is applied in a similar
fashion as the seal coat. After the ethylcellulose coat is applied, the pellets are dried
for an additional 5 to 10 minutes. They are then removed and screened through a
mesh screen to remove agglomerates and oversize particles.
In one embodiment, a final seal coat is applied over the enteric coat and,
optionally, talc is utilized as a final step prior to filling the DVS formulations into a
suitable packaging unit. Suitably, this final seal coat is composed of HPMC and
water, upon drying, is less than about 1 wt% of the total, coated oral dosage unit.
The formulations described herein can be prepared using the techniques
described herein, as well as methods known to those of skill in the art.
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11. Formulations/Kits/Methods of delivery
In another embodiment, the present invention provides products containing the
DVS formulations of the invention.
In one embodiment, the DVS formulations are packaged for use by the patient
or his caregiver. For example, the formulations can be packaged in a foil or other
suitable package and is suitable for mixing into a food product (e.g., applesauce or the
like) or into a drink for consumption by the patient.
In another embodiment, the DVS formulations are suspended in a
physiologically compatible suspending liquid. For oral liquid pharmaceutical
compositions, pharmaceutical carriers and excipients can include, but are not limited
to water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and
the like.
In yet another embodiment, the DVS formulations are filled in capsules,
caplets or the like for oral delivery.
In another embodiment, the present invention provides for the use of the
formulations described herein in the preparation of medicaments, including but not
limited to medicaments useful in the treatment of depression, gastrointestinal side-
effects of venlafaxine in a subject undergoing treatment therewith, and irritable bowel
syndrome.
In another embodiment, the present invention provides for the use of the
formulations described herein in the preparation of medicaments for delivery to a
pediatric or geriatric patient.
In other embodiments, the present invention provides for the use of the
formulations described herein in the preparation of dosing units, including but not
limited to dosing units for oral, transdermal, or mucosal administration.
Also encompassed by one embodiment of the invention are pharmaceutical
packs and kits comprising a container, such as a foil package or other suitable
container, having a formulation described herein in unit dosage form.
In still a further embodiment, the invention provides method of treating a
subject in need thereof by administering an effective dose of the formulations of the
invention. The formulations of the invention are useful in treatment of depression,
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anxiety, panic disorder, generalized anxiety disorder, post traumatic stress disorder,
premenstrual dysphoric disorder, fibromyalgia, agoraphobia, attention deficit
disorder, obsessive compulsory disorder, social anxiety disorder, autism,
schizophrenia, obesity, anorexia nervosa, bulimia nervosa, Gilles de la Tourette
Syndrome, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction,
borderline personality disorder, chronic fatigue syndrome, urinary incontinence, pain,
Shy Drager syndrome, Raynaud's syndrome, Parkinson's disease, and epilepsy. These
formulations are also useful for enhancing cognition or treating cognitive impairment
in a patient, cessation of smoking or other tobacco uses in a patient, treating
hypothalamic amenorrhea in a depressed or non-depressed human female, lowering
the incidence of nausea, vomiting, diarrhea, abdominal pain, headache, vaso-vagal
malaise, or trismus resulting from the oral administration of O-desmethylvenlafaxine
succinate.
Suitably, the formulations of the invention can reduce the gastrointestinal side-
effects of venlafaxine in a subject undergoing treatment therewith comprising
administering to the patent a formulation of the invention. Without wishing to be
bound by theory, it is anticipated that providing an oral dosage unit as described
herein having a core of the sustained release formulation described herein will result
in a composition of the invention which enhances the bioavailability of DVS by
deferring release of most of the DVS until such time as the formulation is in the ileum
and small intestine, while minimizing colonic release. Such a composition is
anticipated to have a delayed release of at least about one hour and a sustained release
over multiple hours to provide a total release of greater than about 85% within about
12 to about 14 hours. It is also anticipated that providing a pelleted oral dosage unit
of the invention will provide low levels of variability (if any) in plasma exposure and
will provide low incidences of nausea and associated side effects.
An effective amount of the oral dosage units of the invention is an amount
sufficient to prevent, inhibit, or alleviate one or more symptoms of the
aforementioned conditions. The dosage amount useful to treat, prevent, inhibit or
alleviate each of the aforementioned conditions will vary with the severity of the
condition to be treated and the route of administration. The dose, and dose frequency
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will also vary according to age, body weight, response and past medical history of the
individual human patient. In general the recommended daily dose range for the
conditions described herein lies within the range of 10 mg to about 1000 mg ODV per
day and more preferably within the range of about 37.5 mg to about 300 mg/day and
still more preferably from about 50 mg to about 200 mg/day. In other embodiments of
the invention the dosage will range from about 30 mg to about 90 mg/day. Dosage is
described in terms of the free base (ODV) and is adjusted accordingly for the
succinate salt (DVS). For example, a 100 mg ODV strength oral dosage unit of the
formulation typically contains about 152 mg of DVS-233. In another example, a 150
mg ODV strength oral dosage unit of the invention typically contains about 228 mg of
DVS-233. In managing the patient, is generally preferred that the therapy be initiated
at a lower dose and increased if necessary. Dosages for non-human patients can be
adjusted accordingly by one skilled in the art.
DVS may also be provided in combination with other active agents including,
e.g., venlafaxine. The dosage of venlafaxine is preferably about 75 mg to about 350
mg/day and more preferably about 75 mg to about 225 mg/day. Still more preferably
the dosage of venlafaxine is about 75 mg to about 150 mg/day. The ratio of DVS will
vary from patient to patient depending upon a patient's response rate, but generally
will be at least 6:1 ODV salt to venlafaxine. Venlafaxine or another active agent
delivered in a regimen with the oral dosage unit of the invention may be formulated
together with the oral dosage unit of the invention, or delivered separately.
Any suitable route of administration can be employed for providing the patient
with an effective amount of DVS. For example, oral, mucosal (e.g., nasal, sublingual,
buccal, rectal or vaginal), parental (e.g., intravenous or intramuscular), transdermal,
and subcutaneous routes can be employed. Preferred routes of administration include
oral, transdermal and mucosal.
DVS can be combined with a pharmaceutical carrier or excipient (e.g.,
pharmaceutically acceptable carriers and excipients) according to conventional
pharmaceutical compounding technique to form a pharmaceutical composition or
dosage form. Suitable pharmaceutically acceptable carriers and excipients include, but
are not limited to, those described in Remington's, The Science and Practice of
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Pharmacy, (Gennaro, A. R., ed., 19th edition, 1995, Mack Pub. Co.) which is herein
incorporated by reference. The phrase "pharmaceutically acceptable" refers to
additives or compositions that are physiologically tolerable and do not typically
produce an allergic or similar untoward reaction, such as gastric upset, dizziness and
the like, when administered to an animal, such as a mammal (e.g., a human).
Oral solid pharmaceutical compositions may include, but are not limited to
starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants,
binders and disintegrating agents. The pharmaceutical composition and dosage form
may also include venlafaxine or a salt thereof as discussed above.
The following examples illustrate exemplary dosage forms of the invention,
and the use thereof. These examples are not a limitation on the present invention.
Example 1: 2% Surelease (Ethylcellulose dispersion)

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Example 2: 3% Surelease (Ethylcellulose dispersion)

Example 3: Enteric Coated Capsule with Hypromellose/Microcrystalline
cellulose pellet core

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This formula is anticipated to have a release of greater than 85% of its
content, in vivo, within 12 hours of the product being taken orally after a 2 hour lag
period and with about 100% release within 20 hours.
Example 4: Superbioavailable Formulations with
Hypromellose/microcrystalline cellulose in core and without Enteric Coat
A. Capsule Dosage Unit with Pellet Core and Delay Coat

B. Tablet Dosage Unit with Delay Coat

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EXAMPLE 5 - BIOAVAILABILITY STUDIES
The compositions of the invention are designed to enhance the bioavailability
of DVS by deferring release of most of the DVS until such time as the formulation is
in the ileum and small intestine, while minimizing colonic release.
This example describes a study performed to assess the absolute
bioavailability of an exemplary sustained release desvenlafaxine succinate
(DVS-SR) formulation and the pharmacokinetics of desvenlafaxine (DV) in
healthy subjects.
In one embodiment the present invention provides an oral dosage unit
composed of a core of the following sustained release DVS formulation having
an enteric coat. In another embodiment, the invention provides an oral dosage
unit comprising a delay release coat over a core composed of the following
sustained release DVS formulation.
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In this single-dose, open label, two period crossover study, subjects
were randomized to receive either a 1 x 100 mg oral tablet of DVS-SR as
described in the table above or a single 50 mg/1 hr intravenous infusion of
desvenlafaxine succinate (DVS) in 0.9% saline in each period. Plasma was
assayed for the total racemic mixture (R+S) and ratio (R/S) of DV. The
absolute bioavailability was calculated from oral and IV AUC values of the
racemic mixture of DVS.
A total of 14 subjects were enrolled and completed the study. DVS-SR
was generally well tolerated. There were no clinically important changes in
routine laboratory tests, vital signs measurements, and ECGs. The 50 mg IV
formulation had a higher Cmax(232 ng/mL) than the 100 mg oral formulation
(160 ng/mL). The half-lives were similar, ranging from 14-15 hours, and the
100 mg oral formulation of DVS-SR had a higher overall exposure (AUCoral
3996 vs. AUCrv 2443 ng*h/mL). The absolute bioavailability of the oral
formulation was 80.5%. The R and S enantiomers were approximately
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equivalent to each other throughout the concentration profiles for both the IV
and oral formulations.
DVS-SR provided good oral bioavailability (80.5%) and an evenly
balanced enantiomeric ratio.
EXAMPLE 6 - BIOAVAILABILITY STUDY IN CANINES
The DVS-233 formula of Example 1 was formulated in a capsule. This
"prototype" DVS-233 capsule was compared in a bioavailability study in dogs to a
DVS-233 SR tablet having a formulation of the table in Example 5, which lacks a
delay or enteric coating. Six female dogs were assigned to this study. The prototype
capsule and SR tablet were administered as a single oral dose to each dog in a
crossover design, approximately 30 minutes after being fed. Blood samples were
drawn at 0 (predose), 0.5,1,2,3,4,6, 8,12 and 24 hours after dosing, plasma was
separated and assayed for O-desmethylvenlafaxine (ODV) content. The
pharmacokinetic parameter (AUC0-oo) was determined for each dog and descriptive
statistics were calculated. The prototype capsule provided approximately 20% higher
total exposure indicating higher bioavailability.
The present invention is not to be limited in scope by the specific
embodiments described herein. Various modifications to these embodiments will be
obvious to one of skill in the art from the description. Such modifications fall within
the scope of the appended claims.
Patents, patent applications, publications, procedures and the like are cited
throughout the application. The disclosures of these documents are incorporated by
reference herein in their entireties. To the extent that a conflict may exist between the
specification and a reference, the language of the disclosure made herein controls.
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CLAIMS:
1. A superbioavailable DVS (O-desmethylvenlafaxine succinate) sustained
release composition comprising a core containing at least DVS and a water insoluble
filler in an oral dosage unit having a delayed release of at least about one hour and a
sustained release over multiple hours to provide a total release of greater than about 85%
within about 12 to about 14 hours.
2. The superbioavailable DVS composition according to claim 1, having a
delayed release of about two hours and a total release of greater than about 95% within
about 12 to about 14 hours.
3. The superbioavailable DVS composition according to claim 1 or claim 2,
wherein said oral dosage unit further comprises a controlled release coat comprising
ethylcellulose.
4. The superbioavailable DVS composition according to claim 3, wherein
said controlled release coat further comprises about 10% by weight hypomellose, based
on the weight of the controlled release coat.
5. The superbioavailable DVS composition according to claim 3 or claim 4,
wherein said controlled release coat comprises about 90% by weight of an ethylcellulose
dispersion, based on the weight of the controlled release coat.
6. The superbioavailable DVS composition according to any of claims 3 to
5, wherein said controlled release coat consists of about 5 to 20% by weight of the oral
dosage unit.
7. The superbioavailable DVS composition according to any of claims 3 to
6, wherein the core comprises DVS and microcrystalline cellulose, and the oral dosage
unit further comprises a controlled release coat and an enteric coat.
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8. The superbioavailable DVS composition according to any of claims 3 to
7, further comprising a seal coat between the core and the controlled release coat.
9. The superbioavailable DVS composition according to any of claims 1 to
8, wherein the core comprises DVS, microcrystalline cellulose and a matrix forming
polymer, and the oral dosage unit further comprises an enteric coat.
10. The superbioavailable DVS composition according to claim 9, wherein
the matrix forming polymer is hypomellose.
11. The superbioavailable DVS composition according to claim 9 or 10,
wherein the core further comprises talc.
12. The superbioavailable DVS composition according to any of claims 1 to
11, wherein the core comprises:
DVS about 44 to 46 wt%
Hypomellose about 12 to 14 wt%
Microcrystalline cellulose about 21 to 22 wt%
Talc about 2 to 4 wt%
Lubricant about 1%, of the total oral dosage
unit.
13. The superbioavailable DVS composition according to any of claims 1 to
11, wherein DVS comprises 40 to 60 wt% of the oral dosage unit.
14. The superbioavailable DVS composition according to any of claims 1 to
13, wherein the oral dosage unit comprises ODV in the range of 37.5 mg to 300mg.
15. The superbioavailable DVS composition according to claim 14 wherein
the oral dosage unit is a 200 mg ODV strength dosage unit.
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16. The superbioavailable DVS composition according to claim 14, wherein
the oral dosage unit is a 150 mg ODV strength dosage unit.
17. The superbioavailable DVS composition according to claim 14, wherein
the oral dosage unit is a 100 mg ODV strength dosage unit.
18. The superbioavailable DVS composition according to claim 14, wherein
the oral dosage unit is a 50 mg ODV strength
dosage unit.
19. The superbioavailable DVS composition according to any of claims 7 to
18, wherein the enteric coat comprises 10 to 20% by weight of the oral dosage unit.
20. The superbioavailable DVS composition according to any of claims 7 to
19, wherein the enteric coat comprises a methacrylic acid co-polymer, Methyl citrate,
sodium hydroxide and talc.
21. The superbioavailable DVS composition according to any of claims 7 to
20, wherein the enteric coat comprises
Eudragit L30D-55 about 7 to 9 wt%
Triethyl citrate about 0.7 to 1 wt%
Sodium hydroxide about 1 to 1.5 wt%
Talc about 4 to 5 wt%, of the oral dosage unit.
22. Use of a superbioavailable DVS composition acccording to any of claims
1 to 21 in preparing a medicament.
23. A method for treating depression in a subject in need thereof, comprising
administering to the patient a composition comprising a superbioavailable DVS
composition according to any of claims 1 to 21.
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24. A method for reducing the gastrointestinal side-effects of desvenlafaxine
in a subject undergoing treatment therewith comprising administering to the patent a
composition comprising a superbioavailable DVS composition according to any of
claims 1 to 21.
25. The method according to claim 24, wherein the gastrointestinal side-
effects are nausea and vomiting.
26. A pharmaceutical pack comprising a container having a superbioavailable
DVS composition according to any of claims 1 to 21.
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An oral, highly bioavailable unit dosage form of O-desmethylvenlafaxine succinate (DVS) having a delayed release
of at least about one hour and a sustained release over multiple hours to provide a total release of greater than about 85 % within about
12 to about 14 hours is described. In one embodiment, the superbioavailable DVS composition has a delayed release of about two
hours and a total release of greater than about 95 % within about 12 to about 14 hours. Use of the formulation in treating depression
and reducing the gastrointestinal side-effects of O-desmethylvenlafaxine (ODV) is also described.