U.S. patent application number 09/950965 was filed with the patent office on 2002-02-28 for extended release formulation.
This patent application is currently assigned to American Home Products Corporation. Invention is credited to Clark, John C., Lamer, John U., Sherman, Deborah M., White, Steven A..
Application Number | 20020025339 09/950965 |
Document ID | / |
Family ID | 27360003 |
Filed Date | 2002-02-28 |
United States Patent
Application |
20020025339 |
Kind Code |
A1 |
Sherman, Deborah M. ; et
al. |
February 28, 2002 |
Extended release formulation
Abstract
This invention relates to a 24 hour extended release dosage
formulation and unit dosage form thereof of venlafaxine
hydrochloride, an antidepressant, which provides better control of
blood plasma levels than conventional tablet formulations which
must be administered two or more times a day and fiber provides a
lower incidence of nausea and vomiting than the conventional
tablets. More particularly, the invention comprises an extended
release formulation of venlafaxine hydrochloride comprising a
therapeutically effective amount of venlafaxine hydrochloride in
spheroids comprised of venlafaxine hydrochloride, microcrystalline
cellulose and, optionally, hydroxypropylmethylcellulose coated with
a mixture of ethyl cellulose and hydroxypropylmethylcellulose.
Inventors: |
Sherman, Deborah M.;
(Plattsburgh, NY) ; Clark, John C.; (Peru, NY)
; Lamer, John U.; (St. Albans, VT) ; White, Steven
A.; (Champlain, NY) |
Correspondence
Address: |
AMERICAN HOME PRODUCTS CORPORATION
FIVE GIRALDA FARMS
PATENT LAW
MADISON
NJ
07940
US
|
Assignee: |
American Home Products
Corporation
|
Family ID: |
27360003 |
Appl. No.: |
09/950965 |
Filed: |
September 12, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09950965 |
Sep 12, 2001 |
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09884412 |
Jun 19, 2001 |
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09884412 |
Jun 19, 2001 |
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09488629 |
Jan 20, 2000 |
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6274171 |
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09488629 |
Jan 20, 2000 |
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08964328 |
Nov 5, 1997 |
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08964328 |
Nov 5, 1997 |
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08821137 |
Mar 20, 1997 |
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60014006 |
Mar 25, 1996 |
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Current U.S.
Class: |
424/457 |
Current CPC
Class: |
Y10S 514/962 20130101;
A61K 9/1652 20130101; A61K 31/137 20130101; A61K 9/5047
20130101 |
Class at
Publication: |
424/457 |
International
Class: |
A61K 009/52 |
Claims
What is claimed is:
1. An encapsulated, extended release formulation of venlafaxine
hydrochloride comprising a pharmaceutically acceptable capsule
containing a therapeutically effective amount of venlafaxine
hydrochloride in spheroids comprised of venlafaxine hydrochloride,
microcrystalline cellulose and, optionally,
hydroxypropylmethylcellulose coated with a mixture of ethyl
cellulose and hydroxypropylmethylcellulose.
2. An extended release formulation according to claim 1 wherein the
spheroids are comprised of from about 6% to about 40% venlafaxine
hydrochloride by weight, about 50% to about 94% microcrystalline
cellulose, NF, by weight, and, optionally, from about 0.25% to
about 1% by weight of hydroxypropylmethylcellulose, USP.
3. An extended release formulation according to claim 1 wherein the
spheroids are coated with from about 2% to about 12% of total
formulation weight of film coating comprised of from about 80% to
about 90% by weight of film coating of ethyl cellulose, NF, and
from about 10% to about 20% by weight of film coating of
hydroxypropylmethylcellulose, USP.
4. An extended release formulation according to claim 1 wherein the
spheroids are comprised of from about 30% to 40% venlafaxine
hydrochloride by weight, about 50% to about 70% microcrystalline
cellulose, NF, by weight, and, optionally, from about 0.25% to
about 1% by weight of hydroxypropylmethylcellulose, USP.
5. An extended release formulation according to claim 4 wherein the
spheroids are coated with from about 2% to about 12% of total
formulation weight of film coating comprised of from about 80% to
about 90% by weight of film coating of ethyl cellulose, NF, and
from about 10% to about 20% by weight of film coating of
hydroxypropylmethylcellulose, USP.
6. An extended release formulation according to claim 1 wherein the
spheroids comprise from about 6% to about 30% venlafaxine
hydrochloride by weight, about 70.1% to about 94% microcrystalline
cellulose, NF, by weight and, optionally, from about 0.25% to about
1% by weight of hydroxypropylmethylcellulose.
7. An extended release formulation according to claim 6 wherein the
spheroids are coated with from about 2% to about 12% of total
weight of film coating comprised of from about 80% to about 90% by
weight of film coating of ethyl cellulose, NF, and from about 10%
to about 20% by weight of film coating of
hydroxypropylmethylcellulose, USP.
8. An extended release formulation according to claim 6 wherein the
spheroids comprise from about 5% to about 25% venlafaxine
hydrochloride and from about 95% to about 75% microcrystalline
cellulose, with an optional amount of from 0.25% to about 1% by
weight of hydroxypropylmethylcellulose.
9. An extended release formulation according to claim 6 wherein the
spheroids comprise from about 6% to about 25% venlafaxine
hydrochloride and from about 94% to about 75% microcrystalline
cellulose, with an optional amount of from 0.25% to about 1% by
weight of hydroxypropylmethylcellulose.
10. An extended release formulation according to claim 6 wherein
the spheroids comprise from about 6% to about 20% venlafaxine
hydrochloride and from about 94% to about 80% microcrystalline
cellulose, with an optional amount of from 0.25% to about 1% by
weight of hydroxypropylmethylcellulose.
11. An encapsulated, extended release formulation of venlafaxine
hydrochloride according to claim 1 having the following dissolution
profile in USP Apparatus 1 (basket) at 100 rpm in purified water at
37.degree. C.:
7 Time (hours) Average % Venlafaxine HCl released 2 <30 4 30-55
8 55-80 12 65-90 24 >80
12. An extended release formulation according to claim 2 wherein
the spheroids are composed of about 37% by weight of venlafaxine
hydrochloride, about 0.5% by weight of hydroxypropylmethylcellulose
2208, and about 62% by weight of microcrystalline cellulose.
13. A composition according to claim 2 wherein the film coating is
comprised of ethyl cellulose (4.81% of total weight) and
hydroxypropylmethylcellulose (0.85% of total weight).
14. A composition according to claim 2 wherein the film coating
comprises 6-8% by weight of total weight.
15. A composition according to claim 2 wherein the film coating is
comprised of ethyl cellulose (2.48% of total weight) and
hydroxypropylmethylcellulose (0.437% of total weight).
16. A composition according to claim 2 wherein film coating
composition is comprised of ethyl cellulose having a 44.0-51.0%
content of ethoxy groups and hydroxypropylmethylcellulose having a
methoxy content of 28.0-30.0% and a hydroxypropoxy group content of
7.0-12.0%.
17. A film coating composition according to claim 2 which is
comprised of about 85% by total weight of film coating of ethyl
cellulose having a 44.0-51.0% content of ethoxy groups, and about
15% by total weight of film coating of hydroxypropylmethylcellulose
having a methoxy content of 28.0-30.0% and a hydroxypropoxy group
content of 7.0-12.0%.
18. A film coating composition according to claim 2 which is
comprised of 85% by weight of ethyl cellulose type HG 2834 and 15%
by weight of hydroxypropylmethylcellulose type 2910.
19. An extended release formulation of venlafaxine hydrochloride
for once daily administration which comprises spheroids containing
37.3% venlafaxine, 62.17% microcrystalline cellulose and 0.5%
hydroxypropylmethylcellulose type 2208, coated with a quantity of a
mixture comprised of 85% ethyl cellulose type HG 2834 and 15%
hydroxypropylmethylcellulose type 2910 sufficient to give coated
spheroids having a dissolution profile which gives the desired
release rate over a 24 hour period.
20. An extended release formulation of venlafaxine hydrochloride
according to claim 2 which provides peak serum levels of up to 150
ng/ml and extended therapeutically effective plasma levels over a
twenty four hour period.
21. A method for providing a therapeutic blood plasma concentration
of venlafaxine over a twenty four hour period with diminished
incidences of nausea and emesis which comprises administering
orally to a patient in need thereof, an encapsulated, extended
release formulation that provides a peak blood plasma level of
venlafaxine in from about four to about eight hours, said
formulation containing venlafaxine hydrochloride as the active
ingredient.
22. A method for eliminating the troughs and peaks of drug
concentration in a patients blood plasma attending the therapeutic
metabolism of plural daily doses of venlafaxine hydrochloride which
comprises administering orally to a patient in need thereof, an
encapsulated, extended release formulation that provides a peak
blood plasma level of venlafaxine in from about four to about eight
hours, said formulation containing venlafaxine hydrochloride as the
active ingredient.
Description
[0001] This application continuation-in-part of application Ser.
No. 08/964,328, filed Nov. 5, 1997, which is a continuation-in-part
of copending application Ser. No. 08/821,137, filed Mar. 20, 1997,
which, in turn, claims priority from Provisional Application No.
60/014,006 filed Mar. 25, 1996.
BACKGROUND OF THE INVENTION
[0002] 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
(Lodin) appears in U.S. Pat. No. 4,966,768. U.S. Pat. No. 4,389,393
discloses sustained release therapeutic compressed solid unit dose
forms of an active ingredient plus a carrier base comprised of a
high molecular weight hydroxypropylmethylcellulose, methyl
cellulose, sodium carboxymethylcellulose and or other cellulose
ether.
[0003] 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 capsule 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, broken into appropriate lengths and transformed into
spheroids using standard spheronization equipment. The spheroids,
after drying, may then be thin-coated to retard dissolution. The
fin-coated spheroids may then be placed in pharmaceutically
acceptable capsules, such as starch or gelatin capsules, in the
quantity needed to obtain the desired therapeutic effect. Spheroids
releasing the drug at different rates may be combined in a capsule
to obtain desired release rates and blood levels. U.S. Pat. No.
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
microcrystalline cellulose wherein the film coating is composed of
ethyl cellulose, optionally, with hydroxypropylmethylcellulose
and/or a plasticizer.
[0004] Venlafaxine,
1-[2-(dimethylamino)-1-(4methoxyphenyl)ethyl]cyclohexa- nol, is an
important drug in the neuropharmacological arsenal used for
treatment of depression. Venlafaxine and the acid addition salts
thereof are disclosed in U.S. Pat. No. 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. La 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 requiting
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 THE INVENTION
[0005] 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.
[0006] 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 (optimally 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 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.
[0007] The use of the one-a-day venlafaxine hydrochloride
formulations of this invention reduces by adaptation, the level of
nausea and incidence of emesis 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.
[0008] The formulations of this invention comprise an extended
release formulation of venlafaxine hydrochloride comprising a
therapeutically effective amount of venlafaxine hydrochloride in
spheroids comprised of venlafaxine hydrochloride, microcrystalline
cellulose and, optionally, hydroxypropylmethylcellulose coated with
a mixture of ethyl cellulose and hydroxypropylmethylcellulose.
Unless otherwise noted, the percentage compositions mentioned
herein refer to percentages of the total weight of the final
composition or formulation.
[0009] More particularly, the extended release formulations of this
invention are those above wherein the spheroids are comprised of
from about 6% to about 40% venlafaxine hydrochloride by weight,
about 50% to about 95% microcrystalline cellulose, NF, by weight,
and, optionally, from about 0.25% to about 1% by weight of
hydroxypropylmethylcellulose, USP, and coated with from about 2% to
about 12% of total weight of film coating comprised of from about
80% to about 90% by weight of film coating of ethyl cellulose, NF,
and from about 10% to about 20% by weight of film coating of
hydroxypropylmethylcellulose, USP.
[0010] A preferred embodiment of this invention are formulations
wherein the spheroids are comprised of about 30% to about 40%
venlafaxine hydrochloride by weight, about 50% to about 70%
microcrystalline cellulose, NT, by weight, and, optionally, from
about 0.25% to about 1% by weight of hydroxypropylmethylcellulose,
USP, and coated with from about 2% to about 12% of total weight of
film coating comprised of from about 80% to about 90% by weight of
film coating of ethyl cellulose, NF, and from about 10% to about
20% by weight of film coating of hydroxypropylmethylcellulose,
USP.
[0011] Another preferred lower dose formulation of this invention
are those wherein the spheroids are comprised less than 30%
venlafaxine hydrochloride. These formulations comprise spheroids of
from about 6% to about 30% venlafaxine hydrochloride by weight,
about 70% to about 94% microcrystalline cellulose, NF, by weight,
and, optionally, from about 0.25% to about 1% by weight of
hydroxypropylmethylcellulose, USP, and coated with from about 2% to
about 12% of total weight of film coating comprised of from about
80% to about 90% by weight of film coating of ethyl cellulose, NF,
and from about 10% to about 20% by weight of film coating of
hydroxypropylmethylcellulose, USP.
[0012] Within this subgroup of lower dose formulations are
formulations in which the spheroids are comprised of from about 6%
to about 25% venlafaxine hydrochloride and from about 94% to about
75% microcrystalline cellulose, with an optional amount of from
0.25% to about 1% by weight of hydroxypropylmethylcellulose.
Another preferred subgroup of spheroids in these formulations
comprises from about 6% to about 25% venlafaxine hydrochloride and
from about 94% to about 75% microcrystalline cellulose, with an
optional amount of from 0.25% to about 1% by weight of
hydroxypropylmethylcellulose. A ether preferred subgroup of
spheroids in these formulations comprises from about 6% to about
20% venlafaxine hydrochloride and from about 94% to about 80%
microcrystalline cellulose, with an optional amount of from 0.25%
to about 1% by weight of hydroxypropylmethylcellulose. Within each
of these subgroups is understood to be formulations in which the
spheroids are comprised of venlafaxine HCT and microcrystalline
cellulose in the amounts indicated, with no
hydroxypropylmethylcellulose present Each of these formulations is
also preferably contained in a gelatin capsule, preferably a bard
gelatin capsule.
DETAILED DESCRIPTION OF THE INVENTION
[0013] 1-[2-(dimethylamino)-1-(4methoxyphenyl)ethyl]cyclohexanol
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 converted 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.
[0014] The extended release formulations of this invention are
comprised of
1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol
hydrochloride in admixture with microcrystalline cellulose and
hydroxypropylmethylcellulose. Formed as beads or spheroids, the
drug containing formulation is coated with a mixture of ethyl
cellulose and hydroxypropylmethyl cellulose to provide, the desired
level of coating, 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, NF, from about
0.25 to about 1 percent hydroxypropylmethylcell- ulose, 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.RTM. PH101), about
one half percent hydroxypropylmethylcellulose 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.
[0015] The film coating is comprised of 80 to 90 percent of ethyl
cellulose, NF and 10 percent hydroxypropylmethylcellulose (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.
[0016] 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. Important characteristics of suitable
hydroxypropylmethylcelluloses include a low viscosity, preferably
less than 10 cps and more preferably 2-5 cps, and a gel temperature
above that of the temperature of the extrudate during extrusion. As
explained below, these and other characteristics which enable the
extrudate to remain moist and soft (pliable) are preferred for the
hydroxypropylmethylcellulose. In the examples below, the extrudate
temperature was generally 50-55.degree. C.
[0017] 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 brs,
60-70% dissolution at 4 hrs and 85-100% dissolution at 8 hrs.
[0018] Numerous spheroid formulations were prepared using different
grades of microcrystalline cellulose and
hydroxypropylmethylcellulose, different ratios of venlafaxine
hydrochloride and filler, different binders such as
polyinylpyrrolidone, 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 extruded cylinders into spheroids.
Addition of hydroxypropylmethylcellulose 2208 -to the venlafaxine
hydrochloride-microcrystalline cellulose mix made production of
spheroids practical.
[0019] The encapsulated formulations of this invention may be
produced in a uniform dosage for a specified dissolution profile
upon oral administration by techniques understood in the art. For
instance, the spheroid components may be blended for uniformity
with a desired concentration of active ingredient, then spheronized
and dried. The resulting spheroids can then be sifted through a
mesh of appropriate pore size to obtain a spheroid batch of uniform
and prescribed size.
[0020] The resulting spheroids can be coated and resifted to remove
any agglomerates produced in the coating steps. During the coating
process samples of the coated spheroids may be tested for their
distribution profile. If the dissolution occurs too rapidly,
additional coating may be applied until the spheroids present a
desired dissolution rate.
[0021] 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 NO. 1
[0022] Venlafaxine Hydrochloride Extended Release Capsules
[0023] A mixture of 44.8 parts ( 88.4% free base) of venlafaxine
hydrochloride, 74.6 parts 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.
[0024] Stir 38.25 parts of ethyl cellulose, NF, HG2834 and 6.75
parts of hydroxypropylmethylcellulose 2910, USP in a 1:1 v/v
mixture of methylene chloride and anhydrous methanol until solution
of the film coating material is complete.
[0025] To a fluidized bed of the uncoated spheroids is applied
0.667 parts of coating solution per part of uncoated spheroids to
obtain extended release, film coated spheroids having a coating
level of 3%.
[0026] The spheroids are sieved to retain the coated spheroids of a
particle size between 0.85 mm to 1.76 mm diameter. These selected
film coated spheroids are filled into pharmaceutically acceptable
capsules conventionally, such as starch or gelatin capsules.
EXAMPLE NO. 2
[0027] Same as for Example 1 except that 1.11 parts of the film
coating solution per part of uncoated spheroids is applied to
obtain a coating level of 5%.
EXAMPLE NO. 3
[0028] Same as for Example 1 except that 1.33 parts of the film
coating solution is applied to 1 part of uncoated spheroids to
obtain a coating level of 6%.
EXAMPLE NO. 4
[0029] Same as for Example 1 except that 1.55 parts of the film
coating solution is applied to 1 part of uncoated spheroids to
obtain a coating level of 7%.
[0030] In the foregoing failed experiments and in Examples 1-4, the
extrusion was carried out on an Alexanderwerk extruder. Subsequent
experiments carried out on Hutt and Nica extruders surprisingly
demonstrated that acceptable, and even improved, spheroids could be
made without the use of an hydroxypropylmethylcellulose.
[0031] In such fierier experiments the applicability of the
invention was extended to formulations wherein the weight
percentage of venlafaxine hydrochloride is 6% to 40%, preferably 8%
to 35%. Thus, the extended release spheroid formulations of this
invention comprise from about 6 to about 40 percent venlafaxine
hydrochloride, from about 50 to about 94 percent microcrystalline
cellulose, NF, optionally, from about 0.25 to about 1 percent
hydroxypropylmethylcellulose, and from about 2 to about 12 percent,
preferably about 3 to 9 percent, film coating.
[0032] Spheroids of the invention were produced having 8.25% (w/w)
venlafaxine hydrochloride and the remainder (91.75%, w/w) being
microcrystalline cellulose, with a coating of from 3 to 5% (w/w),
preferably 4%, of the total weight. The spheroids with 8.25%
venlafaxine hydrochloride and 4% coating were filled into No. 2
white opaque shells with a target fill weight of 236 mg.
[0033] Further spheroids of the invention were produced having
16.5% (w/w) venlafaxine hydrochloride and the remainder (83.5%,w/w)
being microcrystalline cellulose, with a coating of from 4 to 6%
(w/w), preferably 5%, of the total weight. The spheroids 16.5%
venlafaxine hydrochloride and 5% coating were filled into No. 2
white opaque shells with a target fill weight of 122 mg.
[0034] 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.degree. C.
[0035] 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 to 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.
1TABLE 1 Acceptable Coated Spheroid Dissolution Rates Time (hours)
Average % Venlafaxine HCl released 2 <30 4 30-55 8 55-80 12
65-90 24 >30
[0036] Batches of the coated venlafaxine hydrochloride containing
spheroids which have a dissolution rate corresponding to that of
Table 1 are filled into pharmaceutically acceptable 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 mg, 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.
[0037] Dissolution of the venlafaxine hydrochloride ER capsules is
determined as directed in the U.S. Pharmacopoeia (JSP) using
apparatus 1 at 100 rpm on 0.9 L 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 (nm)
against the dissolution medium. A baseline is drawn from 450 am
through 400 nm and extended to 240 nm. The absorbance at the
wavelength of maximum absorbance (about 274 mm) 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.
[0038] The percentage of venlafaxine released is determined from
the equation 1 % Venlafaxine hydrochloride released = ( As ) ( Wr )
( S ) ( V1 ) ( 0.888 ) ( 100 ) ( Ar ) ( V2 ) ( C )
[0039] where As is absorbance of sample preparation, Wr is weight
of reference standard, mg; S is strength of the reference standard,
decimal; V1 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.
[0040] 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.
2TABLE 2 Plasma venlafaxine level (ng/mL) versus time, conventional
tablet (not extended release) versus ER causule 75 mg 2 .times. 75
mg 1 .times. 150 mg (IR) tablet (ER) capsules (ER) capsules Time
(hours) (q 12 h) (q 24 hr) (q 24 h) 0 62.3 55.0 55.8 0.5 76.3 1
135.6 53.3 53.2 2 212.1 69.8 70.9 4 162.0 138.6 133.3 6 114.6 149.0
143.5 8 86.7 129.3 129.5 10 118.4 114.4 12 51.9 105.1 105.8 12.5
74.7 13 127.5 14 161.3 90.5 91.3 16 134.6 78.2 78.5 18 106.2 20
83.6 62.7 63.3 24 57.6 56.0 57.3
[0041] Table 2 shows that the plasma levels of two 75 mg/capsule
venlafaxine hydrochloride ER capsules and one 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 regimen is very similar to that provided by
two immediate release 75 mg tablets of venlafaxine hydrochloride
administered at 12 hour intervals.
[0042] 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 ng/ml,
following administration of (IR) is reached in two hours and falls
rapidly thereafter.
[0043] 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.
3TABLE 3 Plasma Blood Levels in Human Males Having No Prior
Venlafaxine Blood Level Time 1 .times. 50 mg 2 .times. 75 mg 1
.times. 150 mg (Hours) IR tablet ER capsules ER capsule 0 0 0 0 1
27.87 1.3 0 1.5 44.12 6.0 2.2 2 54.83 20.6 12.8 4 66.38 77.0 81.0 6
49.36 96.5 94.4 8 30.06 93.3 86.9 10 21.84 73.2 72.8 12 15.91 61.3
61.4 14 13.73 52.9 51.9 16 10.67 47.5 41.1 20 5.52 35.2 34.0 24
3.56 29.3 28.5 28 2.53 23.4 22.9 36 1.44 11.9 13.5 48 0.66 5.8
5.2
[0044] 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.degree. C. until analysis could be completed.
[0045] To 1 mL of each plasma sample in a plastic tube was added
150 .mu.L of a stock internal standard solution (150 .mu.g/ml).
Saturated sodium borate (0.2 mL) solution was added to 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 HCl 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
.mu.L portion of the mobile phase (23:77 acetonitrile:0.1M
monobasic ammonium phosphate buffer, pH 4.4) was added to each
tube, vortexed, and 50 .mu.L samples were injected on a Superco
Supercoil LC-8-DB, 5 cm.times.4.6 mm, 5 .mu. 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.
EXAMPLE NO. 5
[0046] Manufactured by the techniques described herein, another
preferred formulation of this invention comprises spheroids of from
about 30% to about 35% venlafaxine hydrochloride and from about
0.3% to about 0.6% hydroxypropylmethylcellulose. These spheroids
are then coated with a film coating, as described above, to a
coating level of from about 5% to about 9%, preferably from about
6% to about 8%. A specific formulation of this type comprises
spheroids of about 33% venlafaxine hydrochloride and about 0.5%
hydroxypropylmethylcellulose, with a film coating of about 7%.
[0047] Lower dosage compositions or formulations of this invention
may also be produced by the techniques described herein. These
lower dosage forms may be administered alone for initial titration
or initiation of treatment, prior to a dosage increase. They may
also be used for an overall low-dose administration regimen or in
combination with higher dosage compositions, such as capsule
formulations, to optimize individual dosage regimens.
[0048] These lower dose compositions may be used to create
encapsulated formulations, such as those containing doses of
venlafaxine hydrochloride from about 5 mg to about 50 mg per
capsule. Particular final encapsulated dosage forms may include,
but are not limited to, individual doses of 7.5 mg, 12.5 mg, 18.75
mg, or 28.125 mg of venlafaxine HCl per capsule.
[0049] The spheroids useful in these lower dose formulations may
comprise from about 5% to about 29.99% venlafaxine HCl, preferably
from about 5% to about 25%, from about 75% to about 95%
microcrystalline cellulose, and, optionally from about 0.25% to
about 1.0% hydroxypropylmethylcellulo- se. The spheroids may be
coated as described above, preferably with a film coating of from
about 5% to about 10% by weight. In some preferred formulations,
the spheroids comprise the cited venlafaxine HCl and
microcrystalline cellulose, with no hydroxypropylmethyl
cellulose.
EXAMPLE NO. 6
[0050] Spheroids comprising 16.5% venlafaxine HCl and 83.5%
microcrystalline cellulose were mixed with approximately 50% water
(w/w) to granulate in a Littleford Blender Model FM-50E/1Z
(Littleford Day Inc., P.O. Box 128, Florence, Kent. 41022-0218,
U.S.A.) at a fixed speed of 180 rpm. The blended material was
extruded through a 1.25 mm screen using a Nica
extruder/spheronization machine (Aeromatic-Fielder Division, Niro
Inc., 9165 Rumsey Rd., Columbia, Md. 21045, U.S.A.) for a 12/20
mesh cut after drying. Two portions of the resulting spheroids were
coated with a 5% and 7% coating level, respectively, by techniques
described above using the coating formulation:
4 Ingredient % (w/w) Methylene Chloride 60.000 Methanol Anhydrous
35.500 Ethylcellulose, NF, HG 2834, 50 cps 3.825 Hydroxypropyl
Methylcelluose, 2910 USP, 0.675 6 cps
[0051] The 5% and 7% coated lots were tested for dissolution on a
Hewlett Packard automated dissolution system over a 24 hour period,
resulting in the following dissolution patterns:
5 % Dissoluded % Dissolved Time/hr 16.5%/5% 16.5%/7% 2 12.4 5.6 4
42.8 25.4 8 70.7 60.4 12 82.2 75.4 24 94.3 92.7
EXAMPLE NO. 7
[0052] A formulation of spheroids containing 8.25% venlafaxine HCl
and 91.75% microcrystalline cellulose was prepared according to the
techniques of Example No. 6 and coated with a 5% film coating. In
the Hewlett Packard automated dissolution system these spheroids
provided the following dissolution profile:
6 % Dissolved Time/hr 8.25%/5% 2 4.4 4 24.2 8 62.9 12 77.8 24
93.5
[0053] Thus, the desired dissolution rates of sustained release
dosage forms of venlafaxine hydrochloride, impossible to achieve
with hydrogel tablet technology, has been achieved with the
film-coated spheroid compositions of this invention.
* * * * *