U.S. patent application number 10/631371 was filed with the patent office on 2005-02-03 for tranexamic acid formulations with reduced adverse effects.
This patent application is currently assigned to Xanodyne Pharmacal, Inc.. Invention is credited to Greiwe, Jeffrey S., Heasley, Ralph A., Moore, Keith A..
Application Number | 20050025825 10/631371 |
Document ID | / |
Family ID | 34104084 |
Filed Date | 2005-02-03 |
United States Patent
Application |
20050025825 |
Kind Code |
A1 |
Heasley, Ralph A. ; et
al. |
February 3, 2005 |
Tranexamic acid formulations with reduced adverse effects
Abstract
Tranexamic acid formulated in an oral dosage form with at least
one agent that decreases tranexamic acid release in the stomach.
Such formulations minimize nausea, vomiting, and other adverse
gastric effects that may accompany tranexamic acid therapy, for
example, to treat heavy menstrual bleeding. One embodiment is an
extended release formulation with waxes, polymers, etc. that
prevent a bolus release of tranexamic acid in the stomach. An
alternative embodiment is a delayed release formulation with
polymers that prevent release of tranexamic acid in the acid
environment of the stomach and delay its release until the
formulation reaches the less acid environment of the intestines.
Such formulations enhance patient compliance with therapy because
adverse effects of tranexamic acid therapy are reduced.
Inventors: |
Heasley, Ralph A.; (US)
; Moore, Keith A.; (US) ; Greiwe, Jeffrey S.;
(US) |
Correspondence
Address: |
WOOD, HERRON & EVANS, LLP
2700 CAREW TOWER
441 VINE STREET
CINCINNATI
OH
45202
US
|
Assignee: |
Xanodyne Pharmacal, Inc.
Florence
KY
|
Family ID: |
34104084 |
Appl. No.: |
10/631371 |
Filed: |
July 31, 2003 |
Current U.S.
Class: |
424/468 ;
514/561 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61P 1/00 20180101; A61P 1/12 20180101; A61K 31/195 20130101; A61P
1/10 20180101; A61K 9/2027 20130101; A61P 1/08 20180101; A61P 1/06
20180101; A61P 15/00 20180101 |
Class at
Publication: |
424/468 ;
514/561 |
International
Class: |
A61K 009/22; A61K
031/195 |
Claims
What is claimed is:
1. A composition comprising a pharmaceutically acceptable
ingestable solid formulation comprising tranexamic acid and at
least one agent that modifies the release of tranexamic acid from
the formulation in the gastrointestinal tract.
2. The composition of claim 1 wherein the agent retards the rate of
tranexamic acid release from the composition in the stomach and
intestine.
3. The composition of claim 1 wherein the agent substantially
prevents tranexamic acid release in the stomach.
4. The composition of claim 1 wherein the agent substantially
prevents release of tranexamic acid at a pH<5.5.
5. The composition of claim 1 wherein the agent comprises at least
one of a wax, a polymer, or a time-released matrix.
6. The composition of claim 1 wherein an amount of tranexamic acid
is in the range between about 375 mg to about 1 gram.
7. A composition comprising tranexamic acid in a pharmaceutically
acceptable modified release ingestable formulation.
8. The composition of claim 7 in a delayed release tablet.
9. The composition of claim 7 in an extended release tablet.
10. The composition of claim 7 wherein the formulation is chosen
from at least one of a tablet, a capsule, a granule, a powder, a
pellet, a dragee, a troche, a non-pareil, a sachet, and a pill.
11. A composition comprising tranexamic acid in an ingestable solid
pharmaceutically acceptable formulation with at least one agent in
an amount sufficient to provide extended release of tranexamic acid
from the composition.
12. The composition of claim 11 wherein the at least one agent
reduces the rate of tranexamic release from the composition.
13. The composition of claim 11 wherein the rate is substantially
uniformly reduced.
14. The composition of claim 11 wherein the agent is selected from
at least one of gel-forming polymers, hydratable polymers, water
soluble polymers or water swellable polymers.
15. The composition of claim 11 wherein the polymers are selected
from at least one of hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl
alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose,
hydroxypropylmethylcellulose, methyl cellulose, vinyl
acetate/crotonic acid copolymers, methacrylic acid copolymers,
maleic anhydride/methyl vinyl ether copolymers, derivatives
thereof, and mixtures thereof.
16. The composition of claim 11 wherein a total concentration of
the polymer is in the range of about 5% by weight to about 50% by
weight of the composition.
17. The composition of claim 11 wherein a total concentration of
the polymer is in the range of about 10% by weight to about 35% by
weight of the composition.
18. The composition of claim 11 wherein a total concentration of
the polymer is in the range of about 10% by weight to about 30% by
weight of the composition.
19. The composition of claim 11 wherein the polymer is
hydroxypropylmethylcellulose.
20. A composition comprising tranexamic acid in an ingestable solid
pharmaceutically acceptable formulation with at least one agent
sufficient to delay the release of tranexamic acid from the
composition until encountering a pH>about 5.5.
21. The composition of claim 20 wherein the agent is at least one
of phthalic acid derivatives of vinyl polymers, phthalic acid
derivatives of vinyl copolymers, hydroxyalkylcelluloses,
alkylcelluloses, cellulose acetates, hydroxyalkylcellulose
acetates, cellulose ethers, alkylcellulose acetates, and partial
esters thereof, and polymers and copolymers of lower alkyl acrylic
acids and lower alkyl acrylates, and partial esters thereof.
22. The composition of claim 20 wherein a total concentration of
the at least one agent is in the range of about 1% by weight to
about 20% by weight of the composition.
23 The composition of claim 20 wherein a total concentration of the
at least one agent is in the range of about 5% by weight to about
12% by weight of the composition.
24. The composition of claim 20 wherein a total concentration of
the at least one agent is about 10% by weight of the
composition.
25. A therapeutic method comprising providing to a patient in need
of tranexamic acid therapy an ingestable solid pharmaceutically
acceptable formulation comprising a therapeutic dose of tranexamic
acid and at least one excipient wherein the excipient retards
tranexamic release in the stomach and substantially releases
tranexamic acid in the small intestine thereby reducing the
concentration of tranexamic acid in the stomach during therapy.
26. The method of claim 25 further reducing adverse
gastrointestinal side effects of therapy.
27. The method of claim 25 wherein the at least one excipient
controls release of tranexamic acid in the stomach.
28. The method of claim 25 wherein the at least one excipient
retards release of tranexamic acid in the stomach.
29. The method of claim 25 wherein the therapeutic dose is in the
range of about 375 mg tranexamic acid to about 1 gram tranexamic
acid per dose.
30. The method of claim 25 wherein the dose is administered either
three times a day or four times a day.
31. The method of claim 30 wherein the dose is at least two solid
tablets or one sachet containing granules.
32. A therapeutic method comprising providing tranexamic acid
therapy to a patient in need thereof in a pharmaceutically
acceptable oral formulation comprising at least one excipient
sufficient to result in a decreased stomach concentration of
tranexamic acid after oral ingestion thereby decreasing at least
one gastrointestinal adverse effect of said therapy.
33. The method of claim 32 decreasing a gastrointestinal adverse
effect selected from the group consisting of nausea, vomiting,
diarrhea, constipation, cramping, bloating, and combinations
thereof.
34. The method of claim 32 provided to a patient having
menorrhagia.
35. A method of reducing gastrointestinal adverse side effects
comprising administering an effective amount of an extended release
pharmaceutical composition comprising tranexamic acid and at least
one agent that controls release of tranexamic acid from the
composition in the gastrointestinal tract.
36. A method of reducing gastrointestinal adverse side effects
comprising administering an effective amount of a composition
comprising tranexamic acid in an oral administrable formulation
selected from the group consisting of extended release, delayed
release, and combinations thereof, wherein upon oral administration
tranexamic acid is substantially released in the small
intestine.
37. A method of reducing gastrointestinal adverse side effects
comprising directing oral administration of an effective amount of
a delayed release pharmaceutical composition comprising tranexamic
acid and at least one agent that delays release of tranexamic acid
from the composition until the small intestine.
Description
FIELD OF THE INVENTION
[0001] The invention is directed to therapeutic oral tranexamic
acid formulations that minimize or eliminate undesirable side
effects.
BACKGROUND
[0002] Tranexamic acid (trans-4-(aminomethyl) cyclohexanecarboxylic
acid, Cyklokapron.RTM. (Pfizer) is an antifibrinolytic agent. That
is, it helps to prevent lysis or dissolution of a fibrin clot which
forms in the normal physiologic process of hemostasis. Its
mechanism of action is as a competitive inhibitor of plasminogen
activation, and as a noncompetitive inhibitor of plasmin; both
plasminogen and plasmin are activators of fibrinolyis and active
clot-lysing agents. Tranexamic acid thus helps to stabilize fibrin
clots, which in turn maintains coagulation and helps to control
bleeding.
[0003] Tranexamic acid is used to control excess bleeding, for
example, excess bleeding that occurs during dental procedures in
hemophiliacs and for heavy bleeding during menstruation
(menorrhagia). Women suffering from menorrhagia are typically
treated orally with 500 mg tranexamic acid tablets administered
three of four times daily with a total daily dose ranging from 3
grams/day (two tablets every eight hours) to 6 grams/day (three
tablets every six hours). However, this treatment may cause adverse
gastrointestinal reactions, including nausea, vomiting, diarrhea,
and cramping, etc. These gastrointestinal side effects are due to
the quantity of tranexamic acid introduced into the stomach with
each dose, as well as the large quantity of excipients used in
tablet formulation that are introduced into the stomach. Such side
effects, in addition to the cramping, bloating, pain, and other
symptoms that may accompany menses, are undesirable, and a
formulation of tranexamic acid is needed which will reduce or
eliminate these side effects.
SUMMARY OF THE INVENTION
[0004] Formulations of tranexamic acid which minimize or eliminate
the undesirable gastrointestinal side effects in patients on oral
tranexamic acid therapy, e.g. women treated for menorrhagia (heavy
menstrual bleeding), by modifying the release characteristics of
tranexamic acid are disclosed. One embodiment is an extended
release formulation, also termed a controlled release formulation,
formulated so that the release of tranexamic acid from the dosage
form occurs in an extended or controlled fashion to prevent a bolus
of tranexamic acid being introduced into the stomach and available
for dissolution in the gastric contents. An alternative embodiment
is a delayed release formulation. Delayed release dosage forms are
formulated to minimize or prevent the dissolution of the drug in
the stomach. The release of tranexamic acid is delayed until the
dosage form exits the stomach and reaches the small intestine. Both
extended release dosage forms and delayed release dosage forms are
termed modified release dosage forms. Such modified release
formulations reduce the concentration of tranexamic acid dissolved
in the stomach contents. The beneficial effect of this reduced
tranexamic acid concentration is to lower the amount of tranexamic
acid in the gastric contents so that there are fewer gastric
adverse effects with tranexamic acid therapy. This reduction in
gastric adverse effects results in improved patient compliance with
therapy, because patients will not intentionally miss taking a dose
to avoid these adverse side effects. Physicians will also be more
likely to initiate and maintain tranexamic acid treatment for their
patients because of the reduced patient complaints.
[0005] These and other advantages will be apparent in light of the
following detailed description and examples.
DETAILED DESCRIPTION
[0006] The present invention is a modified release tranexamic acid
tablet for oral administration. The tablet contains at least one
excipient (defined herein as any substance other than the active,
i.e., tranexamic acid) which minimizes or eliminates the adverse
gastrointestinal side effects in patients, for example, women dosed
with oral tranexamic acid for treatment of menorrhagia.
[0007] A modified release product is defined by the United States
Pharmacopeia (USP) as including delayed release products and
extended-(controlled) release products. One embodiment is an
extended release formulation, also called a sustained release
formulation or a controlled release formulation. Extended,
controlled, or sustained release formulations decrease the
concentration of tranexamic acid and excipients dissolved in the
stomach fluids after dosing by controllably releasing tranexamic
acid over a period of time, as opposed to immediate release
formulations which release the entire dose of tranexamic acid all
at once. In immediate release formulations the entire dose and the
soluble components in the dosage form dissolve in gastric fluid and
present a high concentration of solutes for absorption.
[0008] Another embodiment is a delayed release formulation. The
definition of a delayed release dosage form used herein is that
from the USP, Chapter 1151 Pharmaceutical Dosage Forms--Tablets.
The tablet contains one or more coatings, intended to delay the
release of tranexamic acid until the tablet has passed through the
stomach (enteric coatings). A delayed release tablet is a dosage
form that releases tranexamic acid at a time later than immediately
after administration, that is, it exhibits a lag time in
quantifiable plasma tranexamic concentrations. One or more
coating(s) delays the release of tranexamic acid until the dosage
form has passed through the acidic medium of the stomach.
[0009] Delayed release formulations minimize or prevent release of
tranexamic acid in the stomach and delay its release until the
dosage form has emptied from the stomach into the small intestine.
Delayed release formulations include enteric-coated tablets,
enteric-coated capsules, enteric-coated granules, and
enteric-coated spheres (commonly referred to as "tiny little time
pills" or multiparticulate dosage forms).
[0010] The enteric coating is stable under the acidic conditions in
the stomach and releases tranexamic acid only in the less acidic or
substantially neutral medium of the intestine, (e.g., at pH about
5.5 to about 7.5). It disintegrates, erodes, or dissolves,
releasing tranexamic acid only when it encounters the higher pH of
the intestine. Enteric-coated formulations substantially prevent
dissolution of tranexamic acid in the relatively lower pH of the
stomach. Both extended release and delayed release formulations are
modified-release forms that thus minimize or prevent
gastrointestinal reactions and side effects that occur when a dose
of tranexamic acid is ingested and immediately reaches the
stomach.
[0011] As used herein, the terms extended release formulations,
controlled release formulations, or sustained release formulations
are used to describe drug product formulations designed to release
tranexamic acid over a prolonged period of time. The definition of
an extended release tablet used herein is that from the USP,
Chapter 1151, as previously cited. The tablet is formulated in such
a manner as to make tranexamic acid available over an extended
period of time following ingestion. Expressions such as "prolonged
action", "repeat-action", and "sustained release" also describe
such a dosage form. Extended release dosage forms typically allow
reduced dosing frequency as compared to when tranexamic acid is
present in an immediate release dosage from. These extended release
dosage forms may also reduce fluctuations in plasma tranexamic acid
concentrations. Extended release dosage forms may be prepared as a
tablet, capsule, granule, pellet or suspension, and may be packaged
into capsules, sachets, etc. They may be prepared by any
formulation technique where release of the active substance
(tranexamic acid) from the dosage form is modified to occur at a
slower rate than that from an immediate release product. In these
formulations, tranexamic acid release occurs both in the stomach
and intestine, but at a slower rate so that a bolus of dissolved
drug does not reach the lining of the stomach or intestine and
cause adverse effects, or adverse effects occur with a lower
intensity or frequency because of the lower concentration of
tranexamic acid. Hence, adverse effects are reduced, minimized or
eliminated.
[0012] Methods of preparing extended release formulations are known
to one skilled in the art and are found in Modified Release Drug
Delivery Technology, Rathbone, Hadgraft, and Roberts, Eds., Drugs
and the Pharmaceutical Sciences, Vol. 126, Marcel Dekker Inc, New
York, 2003; Modern Pharmaceutics, Third Edition, Banker and Rhodes,
Eds., Drugs and the Pharmaceutical Sciences, Vol. 72, Marcel Dekker
Inc., New York, 1996; Sustained and Controlled Release Drug
Delivery Systems, Robinson, Ed., Drugs and the Pharmaceutical
Sciences, Vol. 6, Marcel Dekker Inc., NY 1978; Sustained Release
Medications, Chemical Technology Review No. 177, Johnson, Ed.,
Noyes Data Corporation 1980; Controlled Drug Delivery, Fundamentals
and Applications, Second Edition, Robinson and Lee, Eds., Marcel
Dekker Inc., New York, 1987, and as described in U.S. Pat. No.
6,548,084, which is expressly incorporated by reference herein in
its entirety. The terms extended release formulation, controlled
release formulation, and sustained release formulation are used
interchangeably herein, unless indicated otherwise.
[0013] An extended release form, one example of a modified release
form, makes tranexamic acid available over an extended period of
time after ingestion. Extended release dosage forms coupled with
the digestion process and the absorption process in the
gastrointestinal tract cause a reduction in the amount of
tranexamic acid in solution in the gastrointestinal tract compared
to dosing tranexamic acid presented as a conventional dosage form
(e.g., as a solution, or as an immediate release dosage form). The
extended release formulation may be verified by in vitro
dissolution testing and in vivo bioequivalence documentation,
according to Food and Drug Administration standards, e.g, as set
forth at www.fda.gov, 21 CFR .sctn.314, 320, and also at USP 23 NF
18 .sctn.711, 724. Briefly, in vitro dissolution is conducted on
twelve individual dosage units. Multipoint dissolution profiles are
obtained using discriminating combinations of apparatus, agitation
speed, and medium. A surfactant may be used if justified. Sampling
times are selected to define the release characteristics of the
dosage form and to assure batch to batch reproducibility. Suitable
equipment for dissolution testing is specified in USP 23 Apparatus
1 (rotating basket); Apparatus 2 (rotating paddle); Apparatus 3
(reciprocating cylinder*), Apparatus 4 (flow-through cell*); and
Apparatus 5 (reciprocating disk*) (*modified testing conditions are
used). Rotation speeds of 50 rpm, 100 rpm and 150 rpm are used with
baskets, and 50 rpm, 75 rpm and 100 rpm are used with paddles. The
temperature is 37.degree. C..+-.0.5.degree. C. The dissolution
volume is 500 ml to 1000 ml. The dissolution medium is aqueous, at
various pH values. The sampling schedule is such that adequate
sampling is performed until either 80% of tranexamic acid is
released or an asymptote is reached.
[0014] Tranexamic acid extended release tablets may be formulated
to provide a dose of tranexamic acid, typically 1-2 grams from one
to two tablets, within about the first one to two hours after the
tablet is ingested. Thus, tranexamic acid release occurs at a
controlled rate over an extended period, e.g., about 60 minutes to
about 120 minutes. The controlled rate of tranexamic acid release
over this period of time is designed to provide a reduced
concentration of tranexamic acid in the stomach while allowing the
absorption of tranexamic acid to occur throughout the
gastrointestinal tract. Absorption of tranexamic acid begins as
soon as tranexamic acid is released from the dosage form and is
dissolved in the gastrointestinal fluids contacting the membranes
which line the gastrointestinal tract. The controlled and extended
release of tranexamic acid from the dosage form and the absorption
of drug by the gastrointestinal mucosa help to maintain low
concentrations of drug in the gastrointestinal fluids. The lowered
concentrations result in lower intensity, frequency, and/or
severity of gastrointestinal adverse side effects. The extended
release of tranexamic acid from the dosage form in the stomach and
the upper small intestine, the natural emptying of gastric juice
containing any dissolved tranexamic acid from the stomach, and the
absorption of tranexamic acid from a larger segment of the
gastrointestinal tract (i.e., both the stomach and the small
intestine, rather than the stomach only or the lower portion of the
small intestine if an extended release dosage form with a longer
release time was used), results in reduced levels of dissolved
tranexamic acid in the region of the gastrointestinal tract
proximal or distal to the dosage form. Reduced concentrations of
tranexamic acid along the gastrointestinal tract reduces adverse
gastrointestinal effects associated with oral tranexamic acid
therapy.
[0015] As used herein, the term delayed release formulation
indicates any formulation technique where release of the active
substance (tranexamic acid) from the dosage form is modified so
that release occurs at a later time than that from a conventional
immediate release product. One example of a delayed release
formulation is an enteric coated formulation. Enteric coatings on
the dosage form are intended to control the region of the
gastrointestinal tract where dissolution and subsequent absorption
of tranexamic acid from the enteric coated dosage form occurs.
Enteric coatings can be prepared to substantially prevent
dissolution of the dosage form contents in the stomach. These
coatings function by incorporating materials in the enteric coating
which allow the enteric coating to remain substantially intact in
the acidic environment of the stomach. This substantially intact
enteric coating minimizes or prevents the dissolution of tranexamic
acid in stomach contents. Enteric coatings are formulated to
release the contents of the dosage form when the pH of the
gastrointestinal fluid increases. This increase in pH typically
occurs when the dosage form passes out of the stomach into the
small intestine. That is, the coating remains intact in the
relatively more acidic stomach pH (pH.ltoreq.2) and disintegrates,
dissolves, or is otherwise removed in the relatively less acidic pH
of the intestine (pH.gtoreq.2 about 5 for the upper regions of the
small intestine and pH values from about 7 to about 8.5 in the
lower regions of the intestines). Formulations can be prepared
using enteric coatings intended to release tranexamic acid at pH
values of about 5.5 to about 6.5 or at higher pH values that
typically occur in the lower regions of the intestines. In those
delayed release formulations intended to dissolve at pH 5.5 to
about 6.5 or higher, tranexamic acid release occurs substantially
only upon reaching the duodenum (the upper portion of the small
intestine) so that substantially no tranexamic acid is released in
the stomach, thus minimizing or eliminating adverse effects.
[0016] Tranexamic acid formulated as delayed release tablets may
contain an enteric coating which disintegrates, dissolves, or
erodes at neutral or slightly acidic or slightly alkaline pH, and
thereby allows dissolution of tranexamic acid upon leaving the
stomach, that is, upon stomach emptying into the small intestine.
The release of tranexamic acid in the intestine reduces
gastrointestinal side effects associated with the large dose of
tranexamic acid quickly released into the stomach. Patients treated
with enteric coated formulations of tranexamic acid for delayed
release should be cautioned to not consume antacids while under
tranexamic therapy, because antacids will change the stomach pH and
thus alter the site of tablet dissolution or disintegration. Other
types of delayed release formulations are available, and the above
example is not limiting.
[0017] A delayed release form, another example of a modified
release form, makes tranexamic acid available at a time other than
immediately following oral administration. As for extended release
formulations, delayed release formulations may be verified by in
vitro dissolution testing and in vivo bioequivalence documentation
according to the standard available as previously set forth (USP 23
NF 18, .sctn..sctn.711, 724). When the guidance refers to
dissolution testing in addition to application/compendial release
requirements, the dissolution test should be performed in 0.1 N HCl
for two hours (acid stage), followed by testing in USP buffer media
at a pH range between 4.5 to 7.5 (buffer stage) under standard
(application/compendial) test conditions and increased agitation
speeds using the application/compendial test apparatus. For the
rotating basket method (Apparatus 1) a rotation speed of 50 rpm,
100 rpm, and 150 rpm may be used, and for the rotating paddle
method (Apparatus 2) a rotation speed of 50 rpm, 75 rpm, and 100
rpm may be used. Multipoint dissolution profiles should be obtained
during the buffer stage of testing. Adequate sampling should be
performed, e.g., at 15 min, 30 min, 45 min, 60 min, 120 min
(following the time from which the dosage form is placed in the
buffer), until either 80% of the drug is released or an asymptote
is reached.
[0018] Methods of preparing delayed release formulations are known
to one skilled in the art and are found in, for example,
Remington's Pharmaceutical Sciences 16.sup.th Edition, Mack
Publishing Company 1980, Osol, Ed., and the references cited for
extended release formulations.
[0019] As used herein, alleviation of adverse effects using these
formulations indicates any relief in one or more symptoms, such as
decrease in incidence, severity, or duration of symptoms, and is
not limited to absence of symptoms or elimination of symptoms.
Thus, treatment includes any decrease in incidence, duration,
intensity, frequency, etc. of adverse gastrointestinal symptoms
including, but not limited to, nausea, bloating, cramping,
vomiting, diarrhea, and constipation. The formulations may reduce
symptoms at any time during tranexamic acid therapy, but minimized
adverse effects are particularly noted immediately or shortly after
dosing, that is, within the first few hours after dosing. As used
herein, adverse gastrointestinal effects and side effects are used
interchangeably to indicate non-therapeutic effects (i.e., not
relating to any possible beneficial effects due to tranexamic
acid), ranging from unpleasant but tolerable sensations to severe
gastrointestinal symptoms. As used herein, the terms oral
formulations, ingestable formulations, and orally administered
formulations are used interchangeably and include any dosage forms
which are ingested by mouth, including, but not limited to,
tablets, pills, liquids, gelcaps, dragees, capsules, powders,
granules, pellets, etc.
[0020] Delayed release formulations may be enteric coated
tranexamic acid tablets or enteric coated granules. These tablets
may be prepared by coating compressed tablets with a commercial or
specially formulated enteric film coat, for example, a wax,
polymer, and/or a pH-sensitive matrix that meets (USP) and Food and
Drug Administration (FDA) requirements for enteric coated tablets.
The enteric coating permits disintegration of the tranexamic acid
tablets and dissolution of tranexamic acid as a result of the pH
change between the stomach and the duodenum. Tablet excipients
which inhibit rapid release of tranexamic acid in the stomach and
which promote dissolution and release in the intestine may also be
used. These include, but are not limited to, phthalic acid
derivatives such as phthalic acid derivatives of vinyl polymers and
copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose
acetates, hydroxyalkylcellulose acetates, cellulose ethers,
alkylcellulose acetates and partial esters thereof, and polymers
and copolymers of lower alkyl acrylic acids and lower alkyl
acrylates and partial esters thereof. Commercial preparations
intended for the enteric coating of tablets, capsules, and granules
are available from Degussa (Parsippany, N.J.) and Colorcon (West
Point, Pa.). In one embodiment, the polymers are methacrylic acid
copolymers. These are copolymers of methacrylic acid with neutral
acrylate or methacrylate esters such as ethyl acrylate or methyl
methacrylate, for example, methacrylic acid copolymer, Type C, USP
(a copolymer of methacrylic acid and ethyl acrylate having between
46.0% and 50.6% methacrylic acid units), commercially available
from Rohm Pharma as Eudragit.RTM. L 100-55 (as a powder) or L30D-55
(as a 30% dispersion in water). In another embodiment, the polymers
are hydroxypropyl cellulose phthalate, hydroxypropyl
methylcellulose phthalate, cellulose acetate phthalate,
polyvinylacetate phthalate, polyvinylpyrrolidone phthalate, and the
like. One or more pH-dependent excipient(s) are present in amounts
ranging from about 1% by weight to about 20% by weight, from about
5% by weight to about 12% by weight, or in an amount of about 10%
by weight.
[0021] The quantity of pH dependent excipients is sufficient to
produce a delayed release formulation from which the release rate
of tranexamic acid is controlled such that at a pH below about 5
the rate of dissolution is significantly retarded. For methacrylic
acid copolymer, type C, USP (Eudragit.RTM. L 100-55), a quantity of
pH dependent polymer coating may be applied to tablets in the range
between about 2% to about 15% by weight (dry basis). In another
embodiment, the range is between about 3% to about 6% by weight
(dry basis). The pH dependent polymer may have from about 1% to
about 20% of the methacrylic acid carboxyl groups neutralized. In
one embodiment about 3% to about 6% of the binder methacrylic acid
carboxyl groups are neutralized. One or more pH independent
excipients may be present in amounts ranging from about 1% by
weight to about 10% by weight, from about 1% by weight to about 3%
by weight, or in an amount of about 2% by weight. Film-forming or
viscosity enhancing agents may also be present, such as
hydroxypropyl methylcellulose, hydroxypropyl cellulose,
methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate
esters, and the like.
[0022] Excipients may be admixed so as to form a homogeneous
mixture with tranexamic acid and the pH dependent binder.
Excipients include pH independent binders or film-forming agents
such as hydroxypropyl methylcellulose, hydroxypropyl cellulose,
methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate
esters (e.g., the methyl methacrylate/ethyl acrylate copolymers
sold as Eudragit.RTM. (Rohm Pharma), starches, gelatin, sugars such
as glucose, sucrose, and mannitol, silicic acid,
carboxymethylcellulose, and the like, diluents such as lactose,
mannitol, dry starch, microcrystalline cellulose and the like,
surface active agents such as polyoxyethylene sorbitan esters,
sorbitan ethers, and the like, coloring agents, flavoring agents,
lubricants such as talc, calcium stearate, and magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and other
tableting aids. These excipients may be combined with tranexamic
acid to form delayed release tablets.
[0023] In one embodiment of tranexamic tablets, tranexamic acid is
in the range of about 50% by weight to about 95% or more by weight.
In other embodiments, tranexamic acid is in the range of about 70%
by weight to about 90% by weight, or about 70% by weight to about
80% by weight. The pH dependent binder may be in the range of about
5% by weight to about 40% by weight, about 5% by weight to about
25% by weight, or about 5% by weight to about 15% by weight. The
remaining weight may be made up of pH independent binders, fillers,
or other excipients.
[0024] To prepare delayed release tablet formulations, the agent to
control the release of tranexamic acid may be incorporated into the
tablet matrix or coated onto the tablet surface or both. Tablet
formulations prepared with the pH dependent excipient added as a
binder in the tablet matrix are formulated by granulating a blend
of powders composed with the pH dependent binder. Alternatively,
the pH dependent binder may be added as a powder and wet granulated
by addition of a solvent to the powder blend. The powder blend is
formed by combining portions of the powdered components that make
up the tablet. These powders are intimately mixed by dry-blending.
The dry blended mixture is granulated by wet mixing of a solution
of a binding agent with the powder blend. The time for such wet
mixing may be controlled to influence the dissolution rate of the
formulation. For example, the total powder mix time, that is, the
time during which the powder is granulated, may range from about 1
min to about 10 min, or from about 2 min to about 5 min. Following
granulation, the particles are removed from the granulator and
placed in a fluid bed dryer, a vacuum dryer, a microwave dryer, or
a tray dryer for drying. Drying conditions are sufficient to remove
unwanted granulating solvent, typically water, or to reduce the
amount of granulating solvent to an acceptable level. Drying
conditions in a fluid bed dryer or tray dryer are typically about
60.degree. C. The granulate is dried, screened, mixed with
additional excipients such as disintegrating agents, flow agents,
or compression aids and lubricants such as talc, stearic acid, or
magnesium stearate, and compressed into tablets.
[0025] The tablet that contains a delayed release agent within the
tablet matrix may be coated with an optional film-forming agent.
This applied film may aid in identification, mask an unpleasant
taste, allow desired colors and surface appearance, provide
enhanced elegance, aid in swallowing, aid in enteric coating, etc.
The amount of film-forming agent may be in the range of about 2%
tablet weight to about 4% tablet weight. Suitable film-forming
agents are known to one skilled in the art and include
hydroxypropyl cellulose, cellulose ester, cellulose ether, one or
more acrylic polymer(s), hydroxypropyl methylcellulose, cationic
methacrylate copolymers (diethylaminoethyl)
methacrylate/methyl-butyl-met- hacrylate copolymers such as
Eudragit E.RTM. (Rohm Pharma) and the like, The film-forming agents
may optionally contain colorants, plasticizers, fillers, etc.
including, but not limited to, propylene glycol, sorbitan
monooleate, sorbic acid, titanium dioxide, and one or more
pharmaceutically acceptable dye(s).
[0026] In one embodiment, tranexamic acid tablets are coated with
an enteric film coat. Tranexamic acid tablets are formulated by dry
blending, rotary compacting, or wet granulating powders composed of
tranexamic acid and tablet excipients. These powders are compressed
into an immediate release tablet. Coating this immediate release
tablet with an enteric coating renders this tranexamic acid tablet
as a delayed release tablet.
[0027] Extended release formulations of tranexamic acid include
tablets, pellets, granules, capsules, or other oral dosage forms
prepared in such a way to release tranexamic acid in a controlled
manner.
[0028] Extended release tranexamic acid tablets are prepared by
adding a gel-forming or hydratable polymer to a tranexamic tablet
composition. Suitable gel-forming or hydratable polymers include,
but are not limited to, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl
alcohol, etc. This provides a compressed tablet that may or may not
be film-coated. The tablet releases tranexamic acid by diffusion of
tranexamic acid through the tablet matrix, or by erosion of the
tablet matrix, or by a combination of diffusion from and erosion of
the tablet matrix. Alternatively, water-swellable polymers may be
used to form the tablet matrix. Tablets formed with water swellable
polymers release tranexamic acid by diffusion of tranexamic acid
through the tablet matrix, or by erosion of the tablet matrix, or
by a combination of diffusion from and erosion of the tablet
matrix. One or more water-soluble hydrophilic polymer(s) may also
be used. These include polyvinylpyrrolidine, hydroxypropyl
cellulose, hydroxypropylmethylcellulose, now referred to as
hypromellose (e.g., Methocel.TM., Dow Chemical Company), methyl
cellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid
copolymers, maleic anhydride/methyl vinyl ether copolymers,
derivatives thereof and mixtures thereof. In various embodiments,
the polymer is hydroxypropyl cellulose or
hydroxypropylmethylcellulose. The polymer may be
hydroxypropyl-methyl cellulose with a viscosity ranging from about
50 cps to about 200 cps. The polymer may be
hydroxypropylmethylcellulose with a viscosity of 100 cps,
commercially available as Methocel.TM. K 100 LV (Dow Chemical
Company). The amount of polymer in the composition may be in the
range of about 5% by weight to about 50% by weight of the
composition. In various embodiments, the polymer is in the range of
about 10% by weight to about 35% by weight of the composition, or
about 10% by weight to about 30% by weight of the composition.
[0029] The tablet matrix may also contain soluble and insoluble
components to aid in the formulation and/or the extended release
rate of tranexamic acid. The release process may be adjusted by
varying the type, amount, and the ratio of the tablet ingredients
to produce the desired dissolution profile, as known to one skilled
in the art. A coating may be a partially neutralized pH-dependent
binder that controls the rate of tranexamic acid dissolution in
aqueous media across the range of pH in the stomach, which has a pH
of about 2, and the intestine, which has a pH of about 5.5. One or
more pH dependent binders are used to control the dissolution
profile so that tranexamic acid is released slowly and continuously
as the formulation passes through the stomach and gastrointestinal
tract.
[0030] In one embodiment, compressed extended release tablets are
formulated to comply with USP criteria and to be of such a size and
shape to be easy to swallow. The size of the tablet will depend
upon the dose of tranexamic acid that is needed to provide adequate
therapy and the particular formulation and excipients that are
selected to provide the physical properties necessary for tableting
and for extended release. In various embodiments, a compressed
extended release tablet contains from about 500 mg to about 1 gram
of tranexamic acid, or from about 600 mg to about 750 mg of
tranexamic acid. The daily dose of tranexamic acid may be achieved
by taking one or two tablets at each dosing time.
[0031] In one embodiment, the dose of tranexamic acid per tablet is
in the range of about 500 mg to about 1000 mg for tablets and from
about 500 mg to about 1500 mg for a sachet filled with granules. In
another embodiment, the dose of tranexamic acid is in the range of
about 3 grams/day to about 6 grams/day in three or four divided
doses. As an example, a total daily dose of 3 grams tranexamic acid
may be divided into three doses of one tablet each with each tablet
containing 1 gram tranexamic acid, or may be divided into four
doses of one tablet each with each tablet containing 0.775 gram
tranexamic acid. As another example, a total daily dose of 4 gram
tranexamic acid may be divided into three doses of two tablets at
each dose with each tablet containing 0.666 gram tranexamic acid,
or may be divided into four doses of one tablet each with each
tablet containing 1 gram tranexamic acid. As another example, a
total daily dose of 5 gram tranexamic acid may be divided into
three doses of one tablet each with each tablet containing 0.833
gram tranexamic acid, or may be divided into four doses of two
tablets each with each tablet containing 0.625 gram tranexamic
acid. As another example, a total daily dose of 6 gram tranexamic
acid may be divided into three doses of two tablets each with each
tablet containing 1 gram tranexamic acid, or may be divided into
four doses of two tablets each with each tablet containing 0.75
gram tranexamic acid. For ease of swallowing, the dose of
tranexamic acid taken at each dosing time may be delivered by
taking multiple tablets. For example, the 4 gram daily dose may be
delivered by taking two 666.67 mg tablets three times a day or two
500 mg tablets four times a day. Similarly, the 3 gram daily dose
may be achieved by taking two 550 mg tablets three times a day or
two 375 mg tablets four times a day. Alternatively, for ease of
reference, a dose of 600 mg, 650 mg, or 700 mg of tranexamic acid
per tablet may be used. Alternatively, each dose may be delivered
by taking granules containing the prescribed amount of tranexamic
acid presented in a convenient unit dose package. Such examples are
not limiting and other doses within these ranges will be
appreciated by those skilled in the art.
[0032] Alternatively, extended release or delayed release
tranexamic acid formulations may be administered by pellets or
granules in a sachet. Extended release tranexamic acid pellets or
granules may be prepared by using excipients to control the release
of tranexamic acid from the granule or pellet matrix. Extended
release preparations may also be formulated using coatings to
control the release of tranexamic acid from the granule or pellet.
Delayed release formulations may be prepared by incorporating
excipients to control the release of tranexamic acid in the matrix
of the granule or pellet, or as coating materials on the surface of
the granule or pellet. U.S. Pat. No. 6,433,215, which is expressly
incorporated by reference herein in its entirety, discloses a
method of building layers of drug and binder on sugar spheres and
coating them with a membrane to form a film coating. Such a coating
may be used for either an extended release formulation or a delayed
release formulation, and/or for pharmaceutical elegance. U.S. Pat.
Nos. 5,650,174; 5,229,135; and 5,242,337, each of which is
expressly incorporated by reference herein in its entirety,
disclose variations on fabricating a pellet or nonpareil dosage
form. Spheres are filled into packets, termed sachets, which are
filled by weight to contain the prescribed dose of drug.
Multiparticulates may be coated with an extended release coating or
a delayed release coating, as disclosed in U.S. Pat. No. 6,066,339,
which is expressly incorporated by reference herein in its
entirety. Coated multiparticulates may be packaged in capsules or
sachets. The formulation of granules or pellets for extended or
delayed release is described in Multiparticulate Oral Drug
Delivery, Ghebre-Sellassie, Ed. in Drugs and the Pharmaceutical
Sciences, Vol. 65, Marcel Dekker Inc., NY, 1994 and in the relevant
parts of the references for extended release formulations and
delayed release formulations previously cited and the relevant
portions incorporated herein by reference.
[0033] The inventive tranexamic acid formulations may be used for
additional indications other than menorrhagia.
[0034] The invention will be further appreciated with respect to
the following examples.
EXAMPLE 1
[0035] A sustained release formulation includes pH-dependent and
-independent binders. Tranexamic acid (5333 g) is combined with
methacrylic acid copolymer, Type C (Eudragit.RTM. L 100-55 (Rohm
Pharma) (200 g), microcrystalline cellulose (Avicel.RTM.) (142 g),
and polyvinyl pyrrolidone powders (20 g) and intimately mixed in a
Fielder PMA 65 mixer-granulator. The mixture is granulated with a
solution of sodium hydroxide (8 g) in water, and a 30% aqueous
dispersion of methyl methacrylate/ethyl acrylate copolymer
(Eudragit.RTM. NE 30 D (Rohm Pharma) (300 g) is added to the wet
mass. The resulting granulate is dried in an Aeromatic Strea-5
fluid bed drier, screened, and then mixed with croscarmellose
sodium (10 g) and magnesium stearate (10 g). The mixture is
compressed into tablets with a Manesty B tablet press to achieve a
dose of 700 mg tranexamic acid per tablet.
EXAMPLE 2
[0036] A sustained release formulation is prepared according to
Example 1 except that Eudragit.RTM. L 100-55 is reduced to 100 g,
and Eudragit.RTM. NE 30 D is replaced by a 40% aqueous dispersion
of a methyl methacrylate/ethyl acrylate copolymer (Eudragit.RTM. NE
40 D (Rohm Pharma) 200 g).
EXAMPLE 3
[0037] A sustained release formulation is prepared by blending
tranexamic acid 700 mg/tablet with microcrystalline cellulose and
polyvinylpyrrolidine K25, granulating with water, drying, and
blending with croscarmellose sodium and magnesium stearate. The
blend is compressed into tablets and coated with an enteric
coating.
EXAMPLE 4
[0038] An extended release composition is prepared by mixing
tranexamic acid (3000 g) and from about 100 g to about 300 g
Methocel.TM. K 100 LV (Dow Chemical Company). The mixture is dry
blended, and then is granulated using water until proper
granulation is obtained, as known to one skilled in the art. Wet
granules are dried in a fluid bed dryer, sifted, and ground to
appropriate size. Lubricating and flow agents are mixed with the
dried granulation to obtain a final formulation which is compressed
into tablets containing 650 mg of tranexamic acid per tablet.
EXAMPLE 5
[0039] Methocel.TM. K 100 LV (Dow Chemical Company) is loaded into
a mixer and dry blended with tranexamic acid. The mixture is
granulated using water until proper granulation is obtained, as
known to one skilled in the art. The granulation is then dried,
sifted, and ground to appropriate size.
[0040] Talc and magnesium stearate are screened and blended with
dry granulation. The granulation is loaded into a hopper and
compressed into tablets. Tablets are then coated with an aqueous
film coating.
[0041] In the following formulations, 650 mg tranexamic acid
tablets are compressed from the granulation with water added up to
the desired quantity (qs).
[0042] Formulation one contains 50 mg/tablet Methocel.TM. K 100 LV
Premium CR Grade (Dow Chemical Company), 50 mg/tablet lactose
monohydrate, 25 mg/tablet USP talc, and 8 mg/tablet magnesium
stearate.
[0043] Formulation two contains 75 mg/tablet Methocel.TM. K 100 LV
Premium CR Grade (Dow Chemical Company), 50 mg/tablet lactose
monohydrate, 25 mg/tablet USP talc, and 10 mg/tablet magnesium
stearate.
[0044] Formulation three contains 100 mg/tablet Methocel.TM. K 100
LV Premium CR Grade (Dow Chemical Company), 50 mg/tablet lactose
monohydrate, 30 mg/tablet USP talc, and 10 mg/tablet magnesium
stearate.
[0045] Other variations or embodiments of the invention will also
be apparent to one of ordinary skill in the art from the above
descriptions and examples. Thus, the forgoing embodiments are not
to be construed as limiting the scope of this invention.
* * * * *
References