Note: Descriptions are shown in the official language in which they were submitted.
CA 02290974 1999-11-25
WO 99/01120 PCT/IB98/00933
SnmhiIi~Pd Sertraline Compositions
Field of the Invention
This invention relates to a composition comprising sertraline or a phamlaceu-
tically acceptable salt thereof and a solubilizing agent which prevents gel
formation or
otherwise maintains the solubility of sertraline in a use environment
containing
chloride ions. The invention further relates to a method of treating a
psychiatric or
other illness comprising administering sertraline in such a solubilized
composition to a
mammal, including a human patient, in need of such treatment.
Backgro nd of the Invention
Sertraiine is a selective serotonin reuptake inhibitor (SSRI), which is useful
as
an antidepressant and anorectic agent, and in the treatment of obsessive-
compulsive
disorder, premenstrual dysphoric disorder, post-traumatic stress disorder,
chemical
dependencies, anxiety-related disorders, panic and premature ejaculation.
Sertraline is most commonly prescribed for therapy of depressive illness, in
the general dose range 50-200 mglday. Sertraline has an elimination half life
of 23 hr
and is dosed once daily. Commercially, sertraline is available as the
hydrochloride
salt which is undeniably therapeutically effective, many patients having
availed
themselves of the benefits of this drug.
Some forms of sertraline, particularly salts which exhibit high solubility,
can be
problematic, however. Such salts, generally those having an aqueous solubility
in
excess of 10 mglmL, can exhibit a tendency to form a gel andlor exhibit
reduced
solubility (e.g., precipitate as a salt or as the free base having a lower
solubility in the
environment of use than the salt form originally administered) when exposed to
a use
environment containing chloride ions such as the gastrointestinal tract. The
gel itself
tends to dissolve slowly and otherwise releases sertrafine at a slow rate,
thereby
affecting absorption. It is not known whether gelation is the only mechanism
which
impacts the solubility of sertraline in a use environment. However,
therapeutic
difficulties can accordingly arise from administering an immediate-release
dosage
form in vivo if solubility is affected, regardless of mechanism. Problems can
similarly
arise in the case of controlled-release dosage forms since the controlled
release
profile of the dosage form can be altered ut vivo by factor's affe~ng
sotuf~ty_ The
CA 02290974 1999-11-25
WO 99/01120 2 PCT/IB98/00933
unanticipated phenomenon of gelation of sertraiine salts in a chloride ion-
containing
environment can thus create therapeutic difficulties by unexpectedly altering
the
release profile of a dosage form, whether immediate-release or controlled-
release.
The mechanism of sertraline gelation is not well understood, and can be all
the more
problematic therapeutically since the release characteristics of a gei formed
in situ
may not be anticipated.
In particular, gelling of sertraline in sustained-release dosage forms can be
detrimental in those sustained release systems known as non-eroding matrix
systems, reservoir systems, and osmotic systems. In each of these types of
sustained release formulations release of the drug is dependent on transport
of the
drug across a distance within the device (matrix or coating layer) to the
surrounding
fluid. This drug transport can occur by diffusive or convective mechanisms. In
both
mechanisms, formation of a gel can reduce transport by an order of magnitude
or
more and in some cases can result in devices that exhibit incomplete drug
release
(e.g., less than 70% of the total drug in the formulation).
Summary Of The Invention
This invention provides a composition of matter, suitable for administration
to
a mammal, including a human, comprising sertraline or a pharmaceutically
acceptable salt thereof and an amount of an excipient, herein termed a
°solubilizing
agent" sufficient to effect a concentration of dissolved sertraline in a use
environment
containing chloride ions which is at least 1.5 times higher, preferably 2
times higher,
more preferably 3 times higher than the concentration effected by a
comparative
composition of matter (i.e., a control) identical thereto but for the
inclusion of said
solubilizing agent. The use environments mainly intended are the aqueous in
vivo
digestive fluids of the gastrointestinal (GI) tract including the stomach,
small intestine
and large intestine, and aqueous in vitro chloride ion-containing test media,
as further
described below. The compositions are suitable for formulating into oral
dosage
forms including tablets, capsules, multiparticulates, powders for oral
suspension, and
unit dose packets (sometimes referred to in the art as a "sachet°). In
addition the
compositions can be used in liquid dosage forms such as oral solutions or
suspensions and injectable formutations. For making the compositions of this
invention into oral dosage forms, conventional techniques known to the art can
be
CA 02290974 1999-11-25
WO 99/01120 3 PCT/IB98/00933
employed. The composition can additionally comprise other conventional
pharmaceutical ingredients andlor a pharmaceutically acceptable carrier.
By this invention, it has been determined that in cases of dosage forms
containing sertraline salts which form gels or which otherwise exhibit reduced
solubility in a use environment, solubility may advantageously be increased,
and in
some cases solution viscosity may be advantageously decreased, by employing
the
sertraline salt together with a solubilizing agent which increases the
sertrafine's
solubility. The solubilizing agent preferably also maintains solubility,
meaning that
the level of dissolved sertraline in a use environment, regardless of the salt
employed, is head at a concentration greater than or equal to 1.5 times the
concentration of sertraline in a like formulation without solubilizing
excipient, for at
feast 2 hours. For many dosage fomls it may be advantageous to maintain the
sertraline concentration greater than or equal to 1.5 times the concentration
of
sertraline in tike formulations without solubilizing excipient for longer
periods of time
such as 4 hours, 8 hours, 16 hours, or 20 hours, and this can be effected by
the
choice and amount of solubilizing agent. It has otherwise been determined that
in a
chloride ion-containing use environment without a solubilizing agent, for
example a
test environment such as 0.075M sodium chloride solution, sertraline
solubility is
generally less than 10 mgAImL, usually less than 5 mgA/mL, regardless of the
salt
employed, and despite the fact that many of the salts themselves exhibit
solubilities in
pure water (i.e., no chloride ions) well in excess of 10 mgAImL. Solubiiizing
agents
thus could also be construed to be compounds that maintain sertraline
concentrations
of lOmgA/ml or greater in chloride-ion-containing environments of use.
Reference herein to "a solubilizing agent" herein, including the claims, shall
be
understood as also including the use of more than one solubizing agent in a
composition, added separately or as a mixture.
As mentioned above, the term "use environment" can refer to the aqueous in
vivo chloride ion-containing digestive fluids of the stomach, or to an in
vitro chloride
ion-containing aqueous environment used to test a dosage form for its
sertraline
release characteristics. A useful in vitro test environment for purposes of
this
invention is 0.075M sodium chloride. 0.075M sodium chloride is prefer-ed as a
test
medium because of its ready availability and similar chloride ion
concentration to the
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WO 99/01120 4 PCT/IB98100933
lower levels of chloride ions found in the fluids in the GI tract. Blood 8~
Other Bodv
Fluids, Dorothy S. Dittmer, ed., Federation of American Societies for
Experimental
Biology, Washington, D.C., 1961, pp. 404-419. Thus, as an additional feature,
this
invention provides an in vitro test to determine whether a dosage form is
within the
scope of the invention. That is, the invention provides a composition of
matter
comprising sertraline or a pharmaceutically acceptable salt thereof and an
amount of
a solubilizing agent sufficient to produce and to maintain, for at least 2
hours in
0.075M sodium chloride, a concentration of dissolved sertraline which is at
least 1.5
times higher than the concentration effected by a comparative composition of
matter
70 identical thereto but for the inclusion of said solubiiizing agent.
Agitation should be
employed during the test although, as explained below, the degree or type of
agitation is not critical. Salt solution temperature is not believed to be
particularly
critical so long as it is about 37°C, plus or minus 3°C,
throughout the test. Excipients,
including the solubilizing agents) should be at the desired concentration in
the
aqueous test solution prior to adding sertraline and sodium chloride.
Sertraline is
then added to a concentration ranging between 80% to 100% of ifs saturation
concentration in the test solution. This solution should be decanted off or
filtered
away from any solids. To this solution a 3M NaCI solution is slowly added with
stirring until the NaCI concentration in the test solution is 0.075M. The
sertraline
concentration in this test solution after 2 hours is compared with a control
solution
made in the same manner and consisting of the same components except the
solubilizing agent.
Alternatively, a solubilizing excipient can be identified in an in vivo test
such
as a crossover study. !n an in vivo crossover study a solubilized sertraline-
containing dosage form is dosed to half a group of 12 or more humans and,
after an
appropriate washout period (e.g., one week) the same subjects are dosed with a
dosage form otherwise identical but for inclusion of the solubif~zing agent.
The other
half of the group is dosed with the non-soiubilized dosage fomz first,
followed by the
soiubilized dosage form. Maximum concentration in the blood (Cm~ and/or
bioavailability, measured as the area under the curve (AUC) for a plot of the
concentration of sertraline in blood versus time, is detemzined for each
group. By
comparison, assessment of the solubilized dosage form can be made. If the
average
CA 02290974 2002-11-15
55920-52
Cm~ or AUC for the formulation containing the solubilizing agent is greater by
10% or
more than the formulation without the solubilizing agent, then the
sofubi('~zing
excipient is an embodiment of this invention. It is preferred that the C~"~
and/or AUC
be greater by at least 15%, and mare preferred either or both be greater by at
least
.5 20%. The determination of AUC's is a well known procedure and is described,
for
example, in "Pharmacokinetics; Processes and Mathematics," by Peter Welling
(ACS
Monograph 185, Amer. Chem. Soc., Wash. D. C., 196). Thus, as an additional
feature of the invention, the invention provides a composition of matter
comprising
sertraline or a phamlaceutically acceptable salt thereofand an amount of a
117 solubifizing agent sufficient to effect, in vivo, a C",~ and/or an AUC
which is greater
by at least 10% than the Cm~ and/or AUC effected by a comarison composition of
matter (i.e., a control) identical thereto but for the inclusion of said
solubilizing agent.
The invention further provides a method of increasing the solubility of
sertratine in an aqueous chloride ion-containing environment, comprising
1!5 administering said sertraline in a composition of matter comprising
sertraline and a
sofubifrzing agent.
The invention is surprising in that, prior to the invention, it was not known
that
(1 ) the phenomenon of reduced sertraline solubility in chloride ion-
containing
environments existed, nor that (2) any chemical agent existed which would
reduce or
20 prevent sertraline gelation or reduced sertraline solubility in chloride
ion-containing
use environments or otherwise operate to increase sertraline's solubility in
such use
environments. The term "solubilized sertraline~ is used herein to refer to a
composition comprising sertraline or a sertraline salt plus an excipient (i.e.
the
solubilizing agent) which prevents gelation or otherwise increases, and
preferably
25 maintains, the solubility of the sertraline salt in an in vivo or in vitro
chloride ion-
containing use environment. t.ib;ewise, the term "solubil'~ze" is used to
denote that the
solubility of a sertraline salt is being increased by at least 1.5 times in a
use
environment over what it would be in the absence of a solubilizing agent.
The invention is preferred for use with !he aspartate, acetate, and lactate
salts
30 which are salts that exhibit high solubilities in water relative to the
free base. These
salts are disclosed in commonly assigned co-pending Canadian Patent
application
No. 2,290,966.
CA 02290974 2002-11-15
65920-52
6
For convenience and consistency, reference to "sertraline" in terms of thera-
peutic amounts herein, including the claims, is to active sertraline,
abbreviated herein
as "mgA", i.e., the non-salt, non-hydrated free base having a molecular weight
of
306.2. Amounts in mgA can corweniently be converted to equivalent weights for
whatever salt fom~ is desired.
Many soiubiiizing agents useful herein can be grouped into several broad
categories:
'I 0
1. Organic acids and organic acid salts;
2. Partial Glycerides, i.e., less than fully esterified derivatives of
glycerin,
including monoglycerides and diglycerides;
3. Glycerides;
4. Glyceride derivatives;
5. Polyethylene glycol esters;
6. Polypropylene glycol esters;
7. Polyhydric alcohol esters;
8. Polyoxyethylene ethers;
9. Sorbitan esters; and
10. Polyoxyethylene sorbitan esters.
11. Carbonate salts
Qgtailed Description
The amount of solubilizing agent employed in a composition according to the
invention depends on the particular solubiI'~zing agent employed.
In the case of solubilizing agents which are organic acids the preferred
amount of solubifizer can be calculated as a ratio multiplied by the quantity
of
sertraline to be used, wherein the ratio is of organic acid solubility to
solubility of
sertraline salt:
(organic acid or salt solubilitylsertraline or sertraline salt solubility) x
quantity of
sertraline
CA 02290974 2002-11-15
65920-52
7
where the solubilities referred to are in mg/ml. The above expression is
approximate,
and some adjustment may be advantageous for optimization. Generally the above
expression will give a quantity 'which is plus or minus 25% of the final value
employed, although higher quantities of solubifizing agent can be incorporated
without any particular additional advantage. In addition, organic acid salts
can be
added to modify the pH andlor solubility of the organic acid, effectively
optimizing the
solubilization effect of the agents.
For other types of solubilizing agents listed, typically the amount of
solubilizing
110 agent employed in the dosage form will be 1 to '150% by weight of the
amount of
sertraline employed therein, preferably 1 to 100%, mare preferably 3 to 75%.
Amounts of solubilizing agent higher than 150% may be employed, although it is
believed that in most cases no particular advantage would be provided.
Salts of sertraline or excipients that in combination with sertraline aid in
solubilizing sertraline can be beneficial to virtually any type of sertraline
dosage forms
intended for oral administration, including immediate release as well as
controlled
release systems, including (1) sustained-release dosage forms which meter out
sertraline as they progress through the gastrointestinal system and (2)
delayed
release systems which release sertrafine after an initial delay period
following
ingestion. Immediate-release systems are well known and commercially available
in
both solid and liquid formulations. Controlled release dosage forms of
sertraline are
discussed and disclosed in commonly assigned co-pending Canadian Patent
applications Nos. 2,290,966 and 2,290,969,
Solubilized sertraline can enhance release from the dosage form by increasing
the
concentration gradient for diffusive based systems such as matrix dosage forms
and
reservoir dosage forms. Solubii'~zed sertraline can also enhance delivery from
osmotic dosage farms in that a more soluble sertraline can increase the
osmotic
pressure in the care and increase the sertraline concentration in the fluid
that is
:10 pumped or extruded out of the dosage form. In addition, solubifized
sertraline can
benefit sustained-release formulations by aiding absorption of drug from the
G.I.
CA 02290974 1999-11-25
WO 99/01120 $ PCT/IB98/00933
tract. For example, higher concentrations of drug in the colon can increase
absorption due to a higher concentration gradient across the intestinal wail.
It is noted that currently available commercial dosage forms of sertraline are
immediate-release dosage forms containing sertraline hydrochloride. Even
though
the hydrochloride has proven to be very effective, it is possible that dosage
forms
containing the hydrochloride can also benefit by the addition of a
solubilizing agent.
Examples of organic acids useful in the invention include matic, citric,
erythorbic, adipic, glutamic, aspartic, maieic, aconitic, and ascorbic acid.
Preferred
acids are citric, erythorbic, ascorbic, gfutamic, and aspartic. Salts of
organic acids
such as alkalkine earth metal (magnesium, calcium) salts and alkali metal
(lithium,
potassium, sodium) salts are also effective as well as mixtures of organic
acids and
their salts. Calcium salts such as calcium carbonate, calcium acetate, calcium
ascorbate, calcium citrate, calcium gluconate monohydrate, calcium
lactobionate,
calcium gluceptate, calcium levulinate, calcium pantothenate, calcium
proprionate,
calcium phosphate dibasic, and calcium saccharate are preferred organic acid
salts.
Examples of compounds within the other categories mentioned above are
summarized in Table 1.
_. . ._~w.....~.~. .~.~._.. __... , , .
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WO 99/01120 o PCT/IB98/00933
Solubilizing Agents
Class Examples, Chemical Examples; Trade Designation,
Name
(Vendor)
Partial Glyceryl MonocapryiateMonocaprylin (Sigma, Capmul
Glycerides MCM(Abitec), tmwitor 308
(Huts)
C8-C10 Partial GiyceridesCapmuh' MCM (Abitec), lmwitor'~
742
(Hills),
Imwitor~ 988 (Huts)
Glyceryl Monooieate Myverol~' 18-99 (Eastman),
Calgene~'
GMO
(Calgene), Capmul~ GMO(Abitec)
Glyceryl MonolinoleateMyverol 18-92 (Eastman)
Glyceryl Monostearatelmwitor'~ 791 (Huts) Calgene~'
GSO(Calgene}
Glycery Monolaurate Imwitor~' 312 (Huts) Calgene~'
GLO
(Calgene)
Glyceryl Dilaurate Capmul GDL (Abitec)
Glycerides Triacetin Triacetin (Sigma)
Gfyceride PEG-Derivitized GlyceridesCremophor~' RH40, Cremophor'~
RH60
Derivatives (BASS,
Acconon CAS, CA-9, CA-15,
W230,
TGH (Abitec)
Polyglycolized GlyceridesGelucire'~ 44114, 42112,
50113, 53!10,
35110, 48109, 46/07, 62/05,
50102;
Labrasol~ (Gattefosse); Capmul~
360;
36S, 6620, 662S, 10640, 106100
(Abitec)
Polyethylene PEG 200 Monoiaurate, Calgene~' 20-L, Calgene'~
glycol EstersPEG 400 Monolaurate, 40-L,
Calgene~ 60-L
PEG 600 Monolaurate
PEG 200 Monostearate,Calgene~' 20-S, Calgene'~
PEG 400 Monostearate,40-S,
Calgene~ 60-S
PEG 600 Monostearate
PEG 200 Dilaurate, Calgene~' 22-L, Calgene~
PEG 42-L
400 Dilaurate, PEG Calgene~ 62-L
600
Dilaurate
PolypropylenePropylene Glycol Captex'~ 200 (Abitec)
Glycol EstersDicaprylate
Polyhydric Diethylene Glycol Calgene~' DGL
Alcohol EstersMonolaurate
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WO 99/01120 1 ~ PCT/IB98/00933
Propylene Glycol Calgene PGML
Monolaurate
Ascorbyl Palmitate Ascorbyl Palmitate (Sigma)
PolyoxyethylenePEG Lauryl Ether Nonionic L-4 (Calgene)
Ethers
PEG Stearyl Ether Nonionic S-20 (Calgene),
Myrj 45, 52,
53, 59 (Sigma)
Sorbitan EstersSorbitan MonolaurateCalgene SML, Span 20 (Sigma)
Sorbitan Monooleate Calgene~ SMO, Span 80 (Sigma)
PolyoxyethylenePOE-20 Sorbitan Calgene~' PSML-20, Span 20(Sigma},
Sorbitan EstersMonolaurate Tween 20 (Sigma), Capmul~
POE-L
(Abitec)
POE-20 Monooleate Tween 80, PSMO-20
Saccharide Sucrose Monolaurate Ryoto LW 1540 CChem Service)
Esters
PhospholipidsPhosphatidyl cholineLecithin (Sigma)
Mixed phospholipids Emphos D70-30C Witco)
Block Co- PEO-PPO Block Pluronic' F-68, F127, L-fit
polymers Copolymers (BASF)
Polyethylene PEG 3350 Various sources
Glycols
In addition other compounds useful as solubilizing agents in the invention are
ethyl propionate, methyl paraben, propyl paraben, propyl gallate,
niacinarnide, ethyl
vanillin, paraaminobenzoic acid, butylated hydroxyanisole, imidurea, and
glycine. It is
also noted that preferred compositions include mixtures of an organic acid
with or
without a corresponding organic acid salt, and one or more of the non-organic
solubilizers listed above or in Table 1. It is also noted that it has
generally been
observed that in order to be most effective the solubilizer should have a
solubility in
the aqueous chtoride-ion containing use environment of at least 1 mglml, and
preferably greater than 5mglml.
A preferred group of solubilizing agents, in addition to the prefer-ed organic
acids previously mentioned, includes those in Table 2.
CA 02290974 1999-11-25
WO 99101120 11 PCT/IB98/00933
Table 22
Prefer-ed Solubilizing Agents
Class Examples, ChemicalExamples, Trade Names (source)
Name
Partial Glyceryl monocapryiateMonocaprylin (sigma), Capmui
Glycerides MCM(Abitec),
Imwitor~ 308 (Huts)
C8-C10 Partial Capmul~' MCM (Abitec), Imwitor~'
Glycerides 742
(Huls),
Imwitor~ 988 (Hills)
Gfyceryl MonostearateImwitor~' 191 (Hills) Calgene'~
GSO(Calgene)
Glyceryl MonolaurateImwitor~' 312 (Huts} Calgene~'
GLO
(Calgene)
Glycerides Triacetin Triacetin'~ (Sigma)
Sorbitan EstersSorbitan MonolaurateCalgene~' SML, Span'' 20 (Sigma)
Sorbitan MonoofeateCalgene SMO, Span 80 (Sigma)
PhosphoiipidsPhosphatidyl cholineLecithin' (Sigma)
Mixed phospholipidsEmphos D70-30C Witco)
Block Co- PEO-PPO Block Pfuronic'~ F-68, F127, L-62
polymers Copolymers (BASF)
Polyethylene PEG 3350 Various sources
Glycols
Note: Commercial vendors shown above are as follows:
Abitec Corp. Janesville, WI
BASF, Parsippany, NJ
Calgene Chemical Inc. Skokie, IL
Chem Service, Inc., West Chester, PA
Huls America, Piscataway, NJ
Sigma, St. Louis, MO
Witco, Houston, TX
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WO 99/01120 12 PCT/IB98/00933
Prefer-ed combinations of sotubilizing agents include (1) an organic acid plus
a salt of the same or a different organic acid, (2) an organic acid plus a non-
ionic
sotubilizing agent such as any of those listed in Table 1, and (3) an organic
acid plus
a salt of the same or a different organic acid plus a non-ionic sotubilizing
agent.
Particularly preferred individual solubilizing agents include aspartic acid,
glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid,
citric
acid, glutamic acid, and calcium carbonate. Aspartic acid, glyceryl
monocaprylate,
glyceryl monolaurate and calcium acetate are most preferred.
As previously discussed, a dosage fomz can be tested in vitro to determine
whether an excipient has a solubilizing effect on sertraline in a chloride-ion
containing
use environment and thus is useful as a solubilizing agent. A 0.075M NaCI
solution
is preferred for use as a test medium although other chloride-ion containing
solutions
with equivalent or higher chloride ion concentration than 0.075M (e.g., 0.1 N
HCI or
isotonic saline) may be used to determine the solubilizing effect of a test
excipient. In
some cases reduced solubility is evident simply by adding a dosage form such
as a
powder to the test medium because gelation is visible. Similar problems may be
evident in a dosage form such as a tablet if the tablet is, for example, cut
open and
gelation is visible on its open face. A recommended procedure is to initially
make a
solution containing the desired excipients, including solubilizing agent(s).
The
excipients can be at any concentration relevant to the intended dosage form,
but are
typically for organic acids and soluble salts or sugars 80-100% of saturation.
For
other surfactant-like compounds, concentrations typically range from 1 to 150%
of the
sertraline concentration in the test solution. Sertraline is added to this
excipient-
containing solution at a concentration typically 80-100% of saturation. The
solution is
filtered or decanted to remove any solids and then a 3M solution of sodium
chloride is
added until the sodium chloride concentration is 0.075M. The concentrated
sodium
chloride solution should be added dropwise with stirring. This test medium
should be
kept at a temperature on the order of 37°C for at least 2 hours at
which time the
sertraline concentration in solution is determined. It is preferred that the
sertraline
concentration be maintained for 4 hours, more preferably for 8 hours, still
more
preferably for 16 hours, and most preferably for at least 20 hours. The amount
of
agitation is not critical. When sampling the test medium, filtration or
centrifugation
CA 02290974 1999-11-25
WO 99/01120 ~3 PCTIIB98100933
can be employed to obtain solution that is free of any solids or gel material,
and also
to avoid inclusion of particulates (which may contain sertraline) in the
sample.
Analysis of the samples to determine sertraline concentration can be
accomplished
via several conventional analytical methods, such as by high performance
liquid
chromatography (HPLC). For example, sertraline concentrations can be
determined
using reverse phase HPLC with a ULTRACAR6~ 5 ODS 4.6 x 250 mm column
(Phenomonex, Tomance, CA), and a mixture of acetic acid, triethylamine,
acetonitrile,
and water as mobile phase, with UV detection at 230 nm. For example, the
mobile
phase can be prepared by combining, with stirring, 2.86 ml of glacial acetic
acid, 3.48
ml of triethylamine, diluting to a liter with water, and filtering and
degassing. Flow
rates are typically on the order of 1.5 mllmin, and retention times about 4
minutes.
Dosage forms with solubif~zing agent can be formulated by conventional tech-
piques. Immediate release dosage forms can be capsules, tablets, multipartic-
ulates, liquid solutions or suspensions. Capsule formulations can be either
soft
geEatin capsules where the sertraline is either dissolved or suspended within
the
capsule core or hard gelatin capsules filled with multiparticufates, tablets
or a liquid
(solution or suspension) fill. Immediate release tablets can be by techniques
standard in the industry by simply including the solubilizing agent as one or
more of
the tablet excipients. Likewise immediate-release multiparticulates can be
made that
include solubilizing agents by techniques such as extension spheronization,
rotary
granulation, coating seed cores or other methods common in the pharmaceutical
industry. Liquid formulations consisting of a solution or suspension or both
can be
made by methods common in the pharmaceutical industry.
Controlled-release dosage forms can also be made that include solubilizing
agents by methods common in the pharmaceutical industry. Controlled release
dosage forms include a wide variety of dosage forms that impart control over
the
dissolution rate or rate of release of sertraline from the dosage form. Such
dosage
forms include but are not limited to sustained release, delayed and then
immediate
release, delayed and-then sustained release and a dosage form with a small
portion
of sertraline released immediately and then followed by the majority of the
sertraline
in the dosage release at a sustained rate. Other algorithms of release can
also be
CA 02290974 2002-11-15
65920-52
14
attained such as pulsitile release. Many such formulations are described in
aforementioned c;o-pending Canadian Patent applications Nos. 2,290,966 and
2,290,969.
Standard techniques can be used to make controlled release dosage forms.
For example, tablets can be made by comrnoniy used direct compression methods
that contain sertraline and a solubilizing agent. To provide delayed release,
a pH-
sensitive coating can be applied to these tablets via a side-vented pan coater
(e.g.,
HCT-60 tablet coater, Vector C;arp.). The pH sensitive coating is resistant to
low pH
environments such as typically in the stomach and then dissolves, releasing
sertraline, in neutral pH environment such as typically in the small
intestine. Such
11 l7 coating materials (e.g., cellulose acetate phthalate or methacrykic acid
copolymer) are
common in the pharmaceuticak industry. Aftematively, the tablets can be coated
with
a porous or semipermeable membrane coating to pravide sustained release of the
tablet cores, A particutariy usefuk process for applying a membrane coating
comprises dissolving the coating polymer in a mixture of solvents chosen such
that
7 5 as the coating dries, a phase inversion takes place in the applied coating
solution,
resulting in a membrane with a porous structure. Numerous examples of this
type of
coating system are given in European Patent Specification 0 357 369 B1,
published
March 7, 1990. Many other types of controlled
release dosage forms can also be made that benefit from the inclusion of
solubilizing
20 agents such as matrix systems which include but are not limited to 1 ) non-
eroding
matrices, tablets, multiparticulates and hydrogel-based systems; 2)
hydrophilic
eroding, dispersible or dissolvable matrix systems, tablets and
multiparticuiates; and
3) coated matrix systems. Another class of controlled-release dosage forms
consists
of reservoir systems where release of the drug is modulated by a membrane,
such as
25 capsules and coated tablets or multiparticulates. A third class consists of
osmotic-
based systems such as 1 ) coated bilayer tablets; 2) coated homogeneous tablet
cores; 3) coated multiparticulates; and 4) osmotic capsules_ A fourth class
consists
of swellable systems where drug is release by a swelling and then extrusion of
the
core components out through a passageway in a coating or surrounding shell or
317 outer layer.
The invention is further illustrated by the following examples, which are not
to
be taken as limiting.
CA 02290974 1999-11-25
WO 99101120 15 PCT/IB98/00933
Example 1
This example illustrates that organic acids have the ability to raise the
solubility of the hydrochloride salt of sertraline. The acids were tested by
dissolving
the candidate acid in water and then stirring excess sertraline hydrochloride
in the
acid solution for at least 8 hours. The concentration of sertrafine in the
supernatant
was then measured by HPLC analysis. The results of this test are shown in
Table 1-
1, below. Most of the acids listed in the table successfully raised the
solubility of
sertraline hydrochloride (normal solubility 2.5 mglml).
Table 1-1
Approximate Excipient
Excipient Concentration (mglml)Sertraline Solubility
(mg/ml)
D,L-malic acid 900 21
Citric acid 600 20
Erythorbic acid 400 19
Adipic acid 14 12
Malefic acid 700 6.4
L-aspartic acid 10 5.5
Tartaric acid 1400 5.5
L-giutamic acid 12 5.4
Fumaric acid 11 3.1
Tannic acid 2000 2.8
O, L-tyrosine 600 2.2
Preferred acids, based on the above-described test, are malic, citric,
erythorbic, and
adipic acids. Maieic, L-aspartic, tartaric, and L-glutamic acids also
signifcantly
improved sertraline hydrochloride solubility. Some controlled-release dosage
forms
with such acids in the core will perfoml better than those without such acids.
This is
particularity true for osmotic-based formulations that deliver a solution of
drug.
example 2
This example illustrates that organic acids have the ability to raise the
solubility of the acetate salt of sertraline by a test method similar to that
used for the
hydrochloride salt described in Example 1. The soiubilizing agent, its
concentration,
and resulting sertraline solubility are shown in Table 2-1 below. Based on
these
results, preferred acids to include in a dosage form where increased
sertraiine
CA 02290974 1999-11-25
WO 99/01120 16 PCT/IB98/00933
acetate solubility is desired are ascorbic, erythorbic, citric, lactic,
aspartic, glutamic,
and aconitic acids.
Table 2 1
Excipient ConcentrationSertraiine Solubility
Excipient (mglml) {mglml)
Ascorbic acid 400 >425
Erythorbic acid 400 >330
Citric acid 600 146
Lactic acid 213 >294
Aspartic acid 7 110
Glutamic acid 12 108
Aconitic acid 500 >92
Itaconic acid 150 72
Succinic acid 77 28
None - 64
This example illustrates that organic acids and three calcium salts have the
ability to raise the aqueous solubility of the lactate salt of sertraline
using a method
similar to that used for the hydrochloride salt described in Example 1. The
solubiiizing agent, its concentration in the aqueous test solution, and the
sertraline
lactate solubility in the test solution are fisted in Table 3-1 below.
Solubility of
sertraline lactate in water is approximately 125 mglml. The data below show
that
eight organic acids effected sertraline lactate solubilities about the same as
or higher
than 125 mglml; adipic, erythorbic, itaconic, citric, aspart'c, giutamic,
histidine, and
ascorbic. Also, a solution of a mixture of two of these acids also had high
solubility;
ascorbic and aspartic. Sertraline lactate solubility was also high in calcium
salt
solutions, either alone (calcium citrate) or mixed with ascorbic acid.
. .. ~ .u._ _~ .~...._.....m....~_. r , .
CA 02290974 1999-11-25
WO 99/01120 17 PCT/IB98100933
Excipient ConcentrationSertraline Lactate
Excipient (mglml) Solubility
(mglml)
Adipic acid 14 360
Erythorbic acid 400 >217
Itaconic acid 150 >202
Citric acid 600 162
Aspartic acid 7 >155
Glutamic acid 12 >125
Histidine 42 >116
AscorbiclAspartic400/7 116
Ascorbic 400 102
Glycine 250 66
Aconitic acid 200 <59
Tartaric acid 1400 12
Fumaric acid 11 <9
Sorbic acid 3 <9
Calcium lactate)501400 160
Ascorbic acid
Calcium citrate 10 165
Calcium carbonate)50/400 176
Ascorbic acid
None - 125
1 4
The lower solubility of the sertraline chloride salt and of all sertraline
lactate
and sertraline acetate salts in the presence of high chloride concentrations
suggest
that core formulations are prefer-ed for which sertraline stays in solution
that is, it
does not precipitate or form a gel-like material when chloride is present.
Certain
organic acids and salts were found to inhibit precipitation or gelation of
sertafine when
chloride is present via the following screening test. Sertraline lactate was
dissolved in
water either alone (as a control) or with a candidate solubifizing agent.
Sodium
chloride was then added (as a concentrated solution) and the result observed.
An
exapient was considered beneficial if the solution remained clear and fluid.
The
more chloride that could be added to an excipient solution with the solution
remaining
clear, the more beneficial was the excipient. Table 4-1 below shows the
results of
this screening test, indicating that all the excipients tested increased
sertraline
concentration in the chloride solutions.
CA 02290974 1999-11-25
WO 99101120 1$ PCT/1B98I00933
Table 4-1
Final Sertraline
Excipient ConcentrationObservation
After
1=xcipient ConcentrationConcentration(mglml) NaCI Addition
(mglml) NaCI (mM)
None - 38 22 gellprecipitate
Ascorbic) 40017 152 162 solution
Aspartic
acids
Aspartic 7 114 162 solution
acid
7 152 100 gel
Ascorbic 400 100 102 precipitate
acid
Ascorbic 400/50 150 165 solution
acid)
calcium lactate
Ascorbic 400150 150 170 slightly turbid
acid)
calcium
carbonate
Citric acid)600150 150 162 solution
calcium lactate
Histidine 42 150 110 slight precipitate
Organic compounds (solubilizers) were screened for their ability to enhance
the solubility of sertraiine lactate in aqueous solutions with or without the
presence of
chloride. Excess sertraline lactate was added to an aqueous soiution of the
candidate sofubilizer and, in most cases an organic acid. The organic acids
were
saturated in these solutions and the additional solubilizing agents were at
the
concentration shown in Table 5-1. The equilibrium sertraline solubility was
measured. Then, sodium chloride was added to the saturated solution and the
final
sertraline concentration was measured. The results of these screening tests
are
summarized in Table 5-1.
CA 02290974 1999-11-25
WO 99!01120 PCT/IB98100933
19
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CA 02290974 1999-11-25
WO 99/01120 2~ PCT/IB98I00933
Examlhe 66
This example illustrates that solubilizers for sertratine also can increase
the
rate of dissolution of sertraline. The effect of a candidate excipient on
sertraline
dissolution rate was determined by adding solid drug, the candidate
solubilizing
excipient, and, in some cases, other excipients such as an organic acid and an
osmagent (such as a sugar) to a 1.8 ml centrifuge tube. The sample tubes were
spun at 14K G for 5 minutes in a microcentrifuge to pack the powder. 150 p.i
gastric
buffer was added to the packed powder and the samples were gently agitated,
then
spun at 14K G in a microcentrifuge for 2 minutes. The samples were then
removed
from the microcentrifuge and allowed to stand undisturbed until the solution
was
removed. The solution was removed from the samples after a total of 10 minutes
after gastric buffer was added to the powder pack, and analyzed by HPLC to
determine the sertraline concentration.
The dissolution rate (mg sertralinelmi-min) was calculated from the measured
concentration of dissolved sertraiine in the supernatant as a function of time
over the
first 10 minutes of dissolution. These dissolution rates and the excipient
mixtures far
which they were measured are summarized in Table 6-1 below. As shown, several
excipient mixtures containing solubilizers significantly (about 3X or greater)
increased
the dissolution rate of sertraline, compared with sertraline alone and
compared with
sertra(ine and ascorbic acid.
..
CA 02290974 1999-11-25
WO 99/01120 PCT/IB98/00933
21
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CA 02290974 1999-11-25
WO 99/01120 PCT/IB98/00933
22
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CA 02290974 1999-11-25
WO 99/01120 PCT/IB98/00933
23
Exam Ip a 7
This examples illustrates a method far making osmotic tablets comprising
a tablet core containing sertrafine with and without solubilizing agents
surrounded
by a semipermeable asymmetric membrane coating. In this example the beneft
of incorporating sofubilizers into a controlled-release fomlulation containing
sertraline is demonstrated. Sertraline-hydrochloride was triturated by hand
for 10
minutes with citric acid and microcrystalline cellulose (Avicel PH 102, FMC)
using
a 6 112 inch diameter mortar and pestle. Magnesium stearate was then blended
in
as a lubricant by stirring with a spatula for 60 seconds. The weight ratio of
sertraline-hydrochloride to citric acid to microcrystalline cellulose to
magnesium
stearate was 8.5:63.8:23.7:4; with a total weight of 10 grams. The blended
mixture was pressed into 470 mg tablets in a modified hydraulic jack
(manufactured by Dayton) fitted with a pressure gauge and 318 inch concave
punch under 2500 PSi pressure for 2 seconds. The dimensions of the resulting
tablets were 3/8 inch in diameter and 1l4 inch thick. A semipermeable membrane
coating (as described in U.S. Patent 5,612,059 was applied to these tablets
using
a LDCS-20 pan coater (Vector Corp.) at a spray rate of 20 grams per minute, an
inlet temperature of 40°C and air flow of 40 cfm. The coating solution
contained by
weight 10% Cellulose acetate, (Eastman Chemical, CA398-10), 2.5%
polyethylene glycol (BASF, PEG 3350), 15% water and 72.5% acetone. The
coated tablets were dried 1 hour at 50°C before testing. After drying,
the weight of
applied coating material was 15.4% of the total weight. Additional osmotic
delivery
tablets were prepared by using essentially the same procedure for making the
tablet cores and applying the asymmetric membrane coating to the cores
described above..The composition of the cores and coating solution varied as
shown in Table 7-1. Significant core compositional changes shown include: the
sertraiine salt form, the type and amount of solubiiizer, and the type and
amount of
osmagent. The amount of binder (Avicel~ lubricant (magnesium stearate), and
solubilizer were varied as necessary to obtain good tableting and wetting
properties. These tablets all contained a sertraline dose of 50 mgAltablet.
CA 02290974 1999-11-25
WO 99/01120 PCT/1B98/00933
24
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CA 02290974 1999-11-25
WO 99/01120 PCT/IB98/00933
0
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CA 02290974 1999-11-25
WO 99/01120 26 PCT/IB98/00933
The rates of release of sertraline from these formulations were determined
testing the tablets in a USP Apparatus #2 with paddle stirring speed set at
100 rpm.
The receptor solution used in the dissolution apparatus was 0.13M acetate
buffer at
pH 4.0 with 0.075M sodium chloride kept at 37°C. Samples of the
receptor solution
were taken at the times shown in Table 7-2. Analysis of sertraline released
was
determined by reverse-phase high-performance liquid chromatography (RP HPLC).
The results of release-rate tests performed using these procedures are listed
in Table 7-2. The first two fomZUlations listed, 7a and 7b show low release
rates and
are included as comparison examples. Both these formulations contain a
sertraline
salt (hydrochloride or lactate) and only lactose as the osmagent and no
solubilizing
excipients. The remaining formulations (7c-7h) listed in Table 7-2 all contain
one or
more solubilizing excipients and al( demonstrate significantly higher release
rates of
sertraiine compared with the formulations that do not contain solubilizers.
a Ie 7-2
Fraction
of
Drug
Released
(%)
At
Specified
Time
Tablets
of 0 1 2 4 Hr 8 12 Hr 20
Example Hr Hr Hr Hr Hr
No
7a 0 0 0 0 0 0 0
7b 0 0 1 2 - 10 12
(17
hr)
7c 0 6 15 35 62 76 78
7d 0 0 0 4 19 28 44
7e 0 8 19 37 60 73 83
7f 0 0.7 6 17 37 54 78
7g 0 0.4 4 13 31 41 53
__ 0 8 18 38 56 64 66
7h-
