BACKGROUND OF THE INVENTION
This invention relates to a process for preparing an
encapsulated extended release formulation of venlafaxine
hydrochloride.
Extended release drug formulations are conventionally
produced as compressed tablets by hydrogel tablet technology.
To produce these sustained release tablet drug dosage forms,
the active ingredient is conventionally compounded with
cellulose ethers such as methyl cellulose, ethyl cellulose or
hydroxypropylmethylcellulose with or without other excipients
and the resulting mixture is pressed into tablets. When the
tablets are orally administered, the cellulose ethers in the
tablets swell upon hydration from moisture in the digestive
system, thereby limiting exposure of the active ingredient to
moisture. As the cellulose ethers are gradually leached away
by moisture, water more deeply penetrates the gel matrix and
the active ingredient slowly dissolves and diffuses through
the gel, making it available for absorption by the body. An
example of such a sustained release dosage form of the
analgesic/anti-inflammatory drug etodolac (LodineR) appears
in US patent 4,966,768.
Where the production of tablets is not feasible, it is
conventional in the drug industry to prepare encapsulated
drug formulations which provide extended or sustained release
properties. In this situation, the extended release dosage
forms may be formulated by mixing the drug with one or more

binding agents to form a uniform mixture which is then
moistened with water or a solvent such as ethanol to form an
extrudable plastic mass from which small diameter, typically
1 mm, cylinders of drug/matrix are extruded, chopped into
appropriate lengths and transformed into spheroids using
standard spheronization equipment. The spheroids, after
drying, may then be film-coated to retard dissolution-
Gelatin capsules are filled with the film-coated spheroids in
the quantity needed to obtain the desired therapeutic effect.
Spheroids releasing the drug at different rates may be
combined in a gelatin capsule to obtain desired release rates
and blood levels. US patent 4,138,475 discloses a sustained
release pharmaceutical composition consisting of a hard
gelatin capsule filled with film-coated spheroids comprised
of propanolol in admixture with microcystalline cellulose
wherein the film coating is composed of ethyl cellulose,
optionally with hydroxypropylmethylcellulose and/or a
plasticizer.
Venlafaxine, 1-[2-(dimethylamino)-1-(4-methoxyphenyl)
ethyl]cyclohexanol, is an important drug in the
neuropharmacological arsenal used for treatment of
depression. Venlafaxine and the acid addition salts thereof
are disclosed in US patent 4,535,186. Venlafaxine
hydrochloride is presently administered to adults in
compressed tablet form in doses ranging from 75 to 350
mg/day, in divided doses two or three times a day. In

therapeutic dosing with venlafaxine hydrochloride tablets,
rapid dissolution results in a rapid increase in blood plasma
levels of the active compound shortly after administration
followed by a decrease in blood plasma levels over several
hours as the active compound is eliminated or metabolized,
until sub-therapeutic plasma levels are approached after
about twelve hours following administration, thus requiring
additional dosing with the drug. With the plural daily
dosing regimen, the most common side effect is nausea,
experienced by about forty five percent of patients under
treatment with venlafaxine hydrochloride. Vomiting also
occurs in about seventeen percent of the patients.
BRIEF DESCRIPTION OF TIDE INVENTION
The present invention relates to a process for preparing
an encapsulated, extended release formulation of venlafaxine
hydrochloride comprising incorporation of a therapeutically
effective amount of spheroids comprised of venlafaxine
hydrochloride, microcrystalline cellulose hydroxypropyl
methylcellulose coated with a coating composition comprising
ethyl cellulose and hydroxypropylmethylcellulose, into a hard
gelatin capsule.
In accordance with this invention, there is provided an
extended release (ER), encapsulated formulation containing
venlafaxine hydrochloride as the active drug component, which
provides in a single dose, a therapeutic blood serum level
over a twenty four hour period.
Through administration of the venlafaxine formulation of

this invention, there is provided a method for obtaining a
flattened drug plasma concentration to time profile, thereby
affording a tighter plasma therapeutic range control than can
be obtained with multiple daily dosing. In other words, this
invention provides a method for eliminating the sharp peaks
and troughs (hills and valleys) in blood plasma drug levels
induced by multiple daily dosing with conventional immediate
release venlafaxine hydrochloride tablets. In essence, the
plasma levels of venlafaxine hydrochloride rise, after
administration of the extended release formulations of this
invention, for between about five to about eight hours
(optionally about six hours) and then begin to fall through a
protracted, substantially linear decrease from the peak
plasma level for the remainder of the twenty four hour
period, maintaining at least a threshold therapeutic level of
the drug during the entire twenty-four hour period. In
contrast, the conventional immediate release venlafaxine
hydrochloride tablets give peak blood plasma levels in 2 to 4
hours. Hence, in accordance with the use aspect of this
invention, there is provided a method for moderating the
plural blood plasma peaks and valleys attending the
pharmacokinetic utilization of multiple daily tablet dosing
with venlafaxine hydrochloride which comprises administering
to a patient in need of treatment with venlafaxine
hydrochloride, a one-a-day, extended release formulation of
venlafaxine hydrochloride.

The use of the one-a-day venlafaxine hydrochloride
formulations of this invention reduces by adaptation,
the level of nausea and incidence of ernesis that attend
the administration of multiple daily dosing. In
clinical trials of venlafaxine hydrochloride ER,
the probability of developing nausea in the course of the trials was greatly reduced after the
first week. Venlafaxine ER showed a statistically significant improvement over
conventional venlafaxine hydrochloride tablets in two eight-week and one 12 week clinical
studies. Thus, in accordance with this use aspect of the invention there is provided a
method for reducing the level of nausea and incidence of emesis attending the
administration of venlafaxine hydrochloride which comprises dosing a patient in need of
treatment with venlafaxine hydrochloride with an extended release formulation of
venlafaxine hydrochloride once a day in a therapeutically effective amount.
Detailed Description of the Invention
l-[2-(dimethylamino)- l-(4-methoxyphenyl)ethyl]cycIohexanoI hydrochloride is
polymorphic. Of the forms isolated and characterized to date, Form I is considered to be the
kinetic product of crystallization which can be convened to Form II upon heating in the
crystallization solvent. Forms I and II cannot be distinguished by their melting points but
do exhibit some differences in their infrared spectra and X-ray diffraction patterns. Any of
the polymorphic forms such as Form I or Form II may be used in the formulations of the
present invention.
The extended release formulations of this invention are comprised of l-[2-
(dimethylamino)-l-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride in admixture with
microcrystalline cellulose and hydroxypropylmethylcellulose. Formed ass beads or
spheroids, the drug containing formulation is coated with a mixture of ethyl cellulose and
hydroxypropylmethyl cellulose to provide the desired level of coaling, generally from about
two to about twelve percent on a weight/weight basis of final product or more preferably
from about five to about ten percent (w/w), with best results obtained at from about 6 to
about 8 percent (w/w). More specifically, the extended release spheroid formulations of
this invention comprise from about 30 to 40 percent venlafaxine hydrochloride, from about
50 to about 70 percent microcrystalline cellulose, MP, from about 0.25 to about 1 percent
hydroxypropylmethylcellulose, USP, and from about 5 to about 10 percent film coating,
all on a weight/weight basis. And preferably, the spheroid formulations contain about 35
percent venlafaxine hydrochloride, about 55 to 60 percent microcrystalline cellulose NF
(Avicel® PH101), about one half percent hydroxypropyl methylceilulose 2208 USP (K3,
Dow, which has a viscosity of 3 cps for 2% aqueous solutions, a methoxy content of 19-
24% and a hydroxypropoxy content of 4-13%), and from about 6 to 8 percent film
coating.
Hydioxypropyl Methylcellulose is a derivative of cellulose in which some hydroxy
groups of cellulose are replaced by methoxy (- O - CH3) and some hydroxy groups of
cellulose are replaced by 2-hydroxypropoxy (- O - CH2 - CHOH - CH3). It is
available in several grades that vary in viscosity and extent of substitution. The US
Pharmacopeia (USP) identifies the substitution type of the product by appendinga four.
digit number to the chemical (i.e. nonproprietary) name. The first two digits refer to the
approximate percentage content of the methoxy group (- O - CH3). The second two
digits refer to the approximate percentage content of the hydroxypropoxy group (- O -
CH2 - CHOH - CH3). The percentages are calculated on a dry basis. The USP
specifications are
The film coating is comprised of 80 to 90 percent of ethyl cellulose, NF and 10 to
20 percent hydroxypropyl methylcellulose (2910), USP on a weight/weight basis.
Preferably the ethyl cellulose has a ethoxy content of 44.0-51% and a viscosity of 50 cps
for a 5% aqueous solution and the hydroxypropylmethylcellulose is USP 2910 having a
viscosity of 6 cps at 2% aqueous solution with a methoxy content of 28-30% and a
hydroxypropoxy content of 7-12%. The ethyl cellulose used herein is Aqualon HG 2834.
Other equivalents of the hydroxypropylmethylcelluloses 2208 and 2910 USP and
ethyl cellulose, NF, having the same chemical and physical characteristics as the
proprietary products named above may be substituted in the formulation without changing
the inventive concept.
It was completely unexpected that an extended release formulation containing
venlafaxine hydrochloride could be obtained because the hydrochloride of venlafaxine
proved to be extremely water soluble. Numerous attempts to produce extended release
tablets by hydrogel technology proved to be fruitless because the compressed tablets were
either physically unstable (poor compressibility or capping problems) or dissolved too
rapidly in dissolution studies. Typically, the tablets prepared as hydrogel sustained release
formulations gave 40-50% dissolution at 2 hrs, 60-70% dissolution at 4 hrs and 85-100%
dissolution at 8 hrs.
Numerous spheroid formulations were prepared using different grades of
microcrysta-lline cellulose and hydio.vypiopy! rnethyleeiluiose, different ratios of
venlafaxine hydrochloride and filler, different binders such as polyvinylpyrrolidone,
methylcellulose, water, and polyethylene glycol of different molecular weight ranges in
order to find a formulation which would provide a suitable granulation mix which could be
extruded properly. In the extrusion process, heat buildup occurred which dried out the
extrudate so much that it was difficult to convert the exuuded cylinders into spheroids.
Addition of hydroxypropylmethylcellulose 2208 to the venlafaxine hydrochloride-
microcrystalline cellulose mix made production of spheroids practical.
The following examples are presented to illustrate applicant's solution to the
problem of preparation of the extended release drug containing formulations of this
invention.
Example 1.
VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE CAPSULES
A mixture of 44.8 pans ( 88.4 % free base) of venlafaxine hydrochloride, 74.6
pans of the microcrystalline cellulose, NF, and 0.60 parts of hydroxypropylmethyl
cellulose 2208, USP, are blended with the addition of 41.0 parts water. The plastic mass
of material is extruded, spheronized and dried to provide uncoated drug containing
spheroids.
Stir 38.25 parts of ethyl cellulose, NF, HG2834 and 6.75 parts of hydroxypropyl
methylcellulose 2910, USP in a 1:1 v/v mixture of methylene chloride and anhydrous
methanol until solution of the film coating material is complete.
To a fluidized bed of the uncoated spheroids is applied 0.667 parts of coating
solution per pan of uncoated spheroids to obtain extended release, film coated spheroids
having a coating level of 3%.
The spheroids are sieved to retain the coated spheroids of a panicle size between
0.85 mm to 1.76 mm diameter. These selected film coated spheroids are filled into hard
gelatin capsules conventionally.
Example 2.
Same as for Example 1 except that 1.11 pans of the film coating solution per pan of
uncoated spheroids is applied to obtain a coating level of 5%.
Example 3.
Same as for Example 1 except that 1.33 pans of the film coating solution is applied
to 1 pan of uncoated spheroids to obtain a coating level of 6%.
Example 4.
Same as for Example 1 except that 1.55 pans of the film coating solution is applied
to 1 part of uncoated spheroids to obtain a coating level of 7%.
The test for acceptability of the coating level is determined by analysis of the
dissolution rate of the finished coated spheroids prior the encapsulation. The dissolution
procedure followed uses USP Apparatus 1 (basket) at 100 rpm in purified water at 37°C.
Conformance with the dissolution rate given in Table 1 provides the twenty-four hour
therapeutic blood levels for the drug component of the extended release capsules of this
invention in capsule form. Where a given batch of coated spheroids releases drug too
slowly to comply with the desired dissolution rate study, a portion of uncoated spheroids
or spheroids with a lower coating level may be added tc the batch to provide, after
thorough mixing, a loading dose for rapid increase of blood drug levels. A batch of coated
spheroids that releases the drug too rapidly can receive additional film-coating to give the
desired dissolution profile.

Batches of the coated venlafaxine hydrochloride containing spheroids which have a
dissolution rate corresponding to that of Table 1 are tilled into hard gelatin capsules in an
amount needed to provide the unit dosage level desired. The standard unit dosage
immediate release (IR) tablet used presently provides amounts of venlafaxine hydrochloride
equivalent to 25 mg, 37.5 mg, 50 rng, 75 mg and 100 mg venlafaxine. The capsules of
this invention are filled to provide an amount of venlafaxine hydrochloride equivalent to
that presently used in tablet form and also up to about 150 mg venlafaxine hydrochloride.
Dissolution of the venlafaxine hydrochloride liR capsules is determined as directed
in the U. S. Pharmacopoeia (USP) using apparatus 1 a: 100 10m on 0.9 I. of water. A
filtered sample of the dissolution medium is taken at the times specified. The absorbance of
the clear solution is determined from 240 to 450 nanometers (urn) against the dissolution
medium. A baseline is drawn from 450 nm through 400 nm and extended to 240 nm. The
absorbance at the wavelength of maximum absorbance (about 274 nm) is determined with
respect to this baseline. Six hard gelatin capsules are filled with the theoretical amount of
venlafaxine hydrochloride spheroids and measured for dissolution. Standard samples
consist of venlafaxine hydrochloride standard solutions plus a gelatin capsule correction
solution. The percentage of venlafaxine released is determined from the equation

where As is absorbance of sample preparation, Wr is weight of reference standard, me; S
is strength of the reference standard, decimal; VI is the volume of dissolution medium used
to dissolve the dosage form, mL; 0.884 is the percent free base, Ar is the absorbance of the
standard preparation, V2 is the volume of reference standard solution, mL; and C is the
capsule claim in mg.
Table 2 shows the plasma level of venlafaxine versus time for one 75 mg
conventional Immediate Release (IR) tablet administered every 12 hours, two 75 mg
extended release (ER) capsules administered simultaneously every 24 hours, and one 150
mg extended release (ER) capsule administered once every 24 hours in human male
subjects. The subjects were already receiving venlafaxine hydrochloride according to the
dosage protocol, thus the plasma blood level at zero time when dosages were administered
is not zero.
Table 2 shows that the plasma levels of two 75 mg/capsule venlafaxine
hydrochloride BR capsules and oae 150 mg/capsule. venlafaxine hydrochloride ER capsule
provide very similar blood levels. The data also show that the plasma level after 24 hours
for either extended release regiments very similar to that provided by two immediate
release 75 mg tablets of venlafaxine hydrochloride administered at 12 hour intervals.
Further, the plasma levels of venlafaxine obtained with the extended release
formulation do not increase to the peak levels obtained with the conventional immediate
release tablets given 12 hours apart. The peak level of venlafaxine from (ER), somewhat
below 150 ng/ml, is reached in about six hours, plus or minus two hours, based upon this
specific dose when administered to patients presently under treatment with venlafaxine
hydrochloride (IR). The peak plasma level of venlafaxine, somewhat over 200 rig/ml,
following administration of (IR) is reached in two hours and falls rapidly thereafter.
Table 3 shows venlafaxine blood plasma levels in male human subjects having a
zero initial blood plasma level. Again, a peak blood plasma concentration of venlafaxine is
seen at about 6 hours after dosing with venlafaxine hydrochloride extended release capsules
in the quantities indicated. The subjects receiving the single 50 mg immediate release tablet
showed a peak plasma level occurring at about 4 hours. For comparative purposes, the
plasma levels of venlafaxine for subjects receiving the conventional formulated tablet can be
multiplied by a factor of three to approximate the plasma levels expected for a single dose
of 150 mg. conventional formulation.
The blood plasma levels of venlafaxine were measured according to the following
procedure. Blood samples from the subjects were collected in heparinized evacuated blood
tubes and the tubes were inverted gently several times. As quickly as possible, the tubes
were centrifuged at 2500 rpm for 15 minutes. The plasma was pipetted into plastic tubes
and stored at -20°C until analysis could be completed.
To 1 mL of each plasma sample in a plastic tube was added 150 µL of a stock
internal standard solution (150 µg/ml). Saturated sodium borate (0.2 mL) solution was
added ro each tube and vortexed. Five mL of ethyl ether was added to each tube which
were then capped and shaken for 10 minutes at high speed. The tubes were centrifuged at
3000 rpm for 5 minutes. The aqueous layer was frozen in dry ice and the organic layer
transferred to a clean screw cap tube. A 0.3 mL portion of 0.01 N HC1 solution was added
to each tube and shaken for 10 minutes at high speed. The aqueous layer was frozen and
the organic layer removed and discarded. A 50 mL portion of the mobile phase (23:77
acetonitriIe:0.1M monobasic ammonium phosphate buffer, pH 4.4) was added to each
tube, vortexed, and 50 µL samples were injected on a Supelco Supelcoil LC-8-DB, 5 cm x
4.6 mm, 5 u. column in a high pressure liquid chromatography apparatus equipped with a
Waters Lambda Max 481 detector or equivalent at 229 nm. Solutions of venlafaxine
hydrochloride at various concentrations were used as standards.
Thus, the desired dissolution rate of a sustained release dosage form of venlafaxine
hydrochloride, impossible to achieve with hydrogel tablet technology, has been achieved
with the film-coated spheroid compositons of this invention.
WE CLAIM :
1. A process for preparing an encapsulated; extended
release formulation of venlafaxine hydrochloride comprising
incorporation of a therapeutically effective amount of
spheroids comprised of venlafaxine hydrochloride, micro-
crystalline cellulose and hydroxypropyl methylcellulose
coated with a coating composition comprising ethyl cellulose
and hydroxypropylmethylcellulose, into a hard gelatin
capsule.
2. A process as claimed in claim 1 wherein the spheroids
are composed of 37.3% by weight of venlafaxine hydrochloride
0.5% by weight of hydroxypropylmethylcellulose having a
methoxy content of 19.0% to 24.0 % and a hydroxypropoxy
content of 4.0% to 12.0%, and 62.17% by weight of
microcrystalline cellulose.
3. A process as claimed in claim 1 or 2, wherein the
coating composition is comprised of ethyl cellulose (4.81% of
the weight of the formulation) and hydroxypropylmethyl-
cellulose (0.85% of the weight of the formulation).
4. A process as claimed in claim 1 or 2, wherein the
coating composition is comprised of ethyl cellulose (4.04% of
the weight of the formulation) and hydroxypropylmethyl-
cellulose (0.714% of the weight of the formulation).
5. A process as claimed in claim 1 or 2, wherein the
coating composition is comprised of ethyl cellulose (2.48% of
the weight of the formulation) and hydroxypropylmethyl-
cellulose (0.437% of the weight of the formulation).
6. A process as claimed in claim 1 or 2, wherein the
coating composition comprises a mixture of ethyl cellulose

(85% of total weight of the coating composition), having a
44.0-51.0% content of ethoxy groups, and hydroxypropylmethyl-
cellulose (15% of total weight of the coating composition),
wherein the hydroxypropylmethylcellulose has a methoxy
content of 28.0-30.0% and a hydroxypropoxy group content of
7.0-12.0%.
7. A process as claimed in any of the preceding claims,
wherein the extended release formulation is for once daily
administration and the spheroids contain 37.3% by weight,
calculated on the spheroids, of venlafaxine, 62.17% by
weight, calculated on the spheroids, of microcrystalline
cellulose and 0.5% by weight, calculated on the spheroids, of
hydroxypropylmethylcellulose whose methoxy content is 19.0%
to 24.0% and hydroxypropoxy content is 4.0% to 12.0%, and are
coated with a quantity of a mixture comprised of 85% by
weight of ethyl cellulose and 15% by weight of hydroxypropyl-
methylcellulose whose methoxy content is 28.0% to 30.0% and a
hydroxypropoxy content is 7.0% to 12%, the said quantity
being sufficient to give coated spheroids having a
dissolution profile which gives the desired release rate over
a 24 hour period.
8. A process for preparing an encapsulated, extended
release formulation of venlafaxine hydrochloride,
substantially as herein described, particularly with
reference to the forgoing examples.

A process for preparing an encapsulated, extended release
formulation of venlafaxine hydrochloride comprising
incorporation of a therapeutically effective amount of
spheroids comprised of venlafaxine hydrochloride,
microcrystalline cellulose and hydroxypropyl methylcellulose
coated with ethyl cellulose and hydroxypropylmethylcellulose
into a hard gelatin capsule.