U.S. patent application number 15/369101 was filed with the patent office on 2017-10-19 for sublingual and buccal film compositions.
The applicant listed for this patent is MonoSol Rx, LLC. Invention is credited to Eric Dadey, Garry L. Myers.
Application Number | 20170296482 15/369101 |
Document ID | / |
Family ID | 51528033 |
Filed Date | 2017-10-19 |
United States Patent
Application |
20170296482 |
Kind Code |
A1 |
Myers; Garry L. ; et
al. |
October 19, 2017 |
SUBLINGUAL AND BUCCAL FILM COMPOSITIONS
Abstract
The present invention relates to products and methods for
treatment of various symptoms in a patient, including treatment of
pain suffered by a patient. The invention more particularly relates
to self-supporting dosage forms which provide an active agent while
providing sufficient buccal adhesion of the dosage form. Further,
the present invention provides a dosage form which is useful in
reducing the likelihood of diversion abuse of the active agent.
Inventors: |
Myers; Garry L.; (Kingsport,
TN) ; Dadey; Eric; (Furlong, PA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
MonoSol Rx, LLC |
Warren |
NJ |
US |
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Family ID: |
51528033 |
Appl. No.: |
15/369101 |
Filed: |
December 5, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14196082 |
Mar 4, 2014 |
9511033 |
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15369101 |
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13842543 |
Mar 15, 2013 |
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14196082 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/04 20180101; A61P 25/36 20180101; A61K 9/7007 20130101;
A61K 9/006 20130101; A61K 47/183 20130101; A61K 2300/00 20130101;
A61K 31/485 20130101; A61K 31/485 20130101; A61K 45/06 20130101;
A61K 31/00 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/485 20060101 A61K031/485; A61K 9/00 20060101
A61K009/00; A61K 31/00 20060101 A61K031/00; A61K 47/18 20060101
A61K047/18; A61K 45/06 20060101 A61K045/06 |
Claims
1. A self-supporting film dosage composition comprising: a. a
polymeric carrier matrix; b. a therapeutically effective amount of
an agonist or a pharmaceutically acceptable salt thereof; c. a
therapeutically effective amount of an antagonist or a
pharmaceutically acceptable salt thereof; and d. a chelator or
antioxidant; wherein the ratio of said antagonist to said chelator
or antioxidant is from about 40:1 to about 1:10 by weight.
2. The composition of claim 1, wherein said ratio of said
antagonist to said chelator or antioxidant is from about 4:1 to
about 1:10 by weight.
3. The composition of claim 1, wherein said ratio of said
antagonist to said chelator or antioxidant is from about 5:1 to
about 1:2 by weight.
4. The composition of claim 1, wherein said ratio of said
antagonist to said chelator or antioxidant is from about 1:2 to
about 2:1 by weight.
5. The composition of claim 1, wherein said chelator or antioxidant
is selected from the group consisting of ethylenediaminetetraacetic
acid (EDTA) and salts thereof, proteins, polysaccharides,
polynucleic acids, glutamic acid, histidine, organic diacids,
polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid,
phosphonates, transferrin, desferrioxamine, dibutylhydroxytoluene
(BHT), dibutylated hydroxyanisole (BHA), propyl gallate, sodium
sulfate, citric acid, sodium metabisulfite, ascorbic acid,
tocopherol, tocopherol ester derivatives,
2-mercaptobenzimidazoleand, and combinations thereof.
6. The composition of claim 1, wherein said chelator or antioxidant
is ethylenediaminetetraacetic acid disodium salt.
7. The composition of claim 1, wherein said antagonist is naloxone
or a pharmaceutically acceptable salt thereof.
8. The composition of claim 1, wherein said agonist is
buprenorphine or a pharmaceutically acceptable salt thereof.
9. The composition of claim 1, wherein said antagonist is naloxone
or a pharmaceutically acceptable salt thereof and said agonist is
buprenorphine or a pharmaceutically acceptable salt thereof.
10. The composition of claim 1, wherein said composition comprises
a first region and a second region, said first region comprising
said agonist and said second region comprising said antagonist.
11. A self-supporting film dosage composition comprising: a. a
polymeric carrier matrix; b. a therapeutically effective amount of
buprenorphine or a pharmaceutically acceptable salt thereof; c. a
therapeutically effective amount of naloxone or a pharmaceutically
acceptable salt thereof; and d. a chelator or antioxidant; wherein
the ratio of said naloxone or a pharmaceutically acceptable salt
thereof to said chelator or antioxidant is from about 40:1 to about
1:10 by weight.
12. The composition of claim 11, wherein said ratio of said
naloxone or a pharmaceutically acceptable salt thereof to said
chelator or antioxidant is from about 4:1 to about 1:10 by
weight.
13. The composition of claim 11, wherein said ratio of said
naloxone or a pharmaceutically acceptable salt thereof to said
chelator or antioxidant is from about 5:1 to about 1:2 by
weight.
14. The composition of claim 11, wherein said ratio of said
naloxone or a pharmaceutically acceptable salt thereof to said
chelator or antioxidant is from about 1:2 to about 2:1 by
weight.
15. The composition of claim 11, wherein said chelator or
antioxidant is selected from the group consisting of
ethylenediaminetetraacetic acid (EDTA) and salts thereof, proteins,
polysaccharides, polynucleic acids, glutamic acid, histidine,
organic diacids, polypeptides, phytochelatin, hemoglobin,
chlorophyll, humic acid, phosphonates, transferrin,
desferrioxamine, dibutylhydroxytoluene (BHT), dibutylated
hydroxyanisole (BHA), propyl gallate, sodium sulfate, citric acid,
sodium metabisulfite, ascorbic acid, tocopherol, tocopherol ester
derivatives, 2-mercaptobenzimidazoleand combinations thereof.
16. The composition of claim 11, wherein said chelator or
antioxidant is ethylenediaminetetraacetic acid disodium salt.
17. The composition of claim 11, further comprising a buffer in an
amount sufficient to maximize the absorption of the buprenorphine
or a pharmaceutically acceptable salt thereof.
18. The composition of claim 11, further comprising a buffering
system comprising a buffer capacity sufficient to inhibit the
absorption of said naloxone or a pharmaceutically acceptable salt
thereof during the time which said composition is in the oral
cavity of a user.
19. The composition of claim 11, wherein said composition comprises
a first region and a second region, said first region comprising
said buprenorphine or a pharmaceutically acceptable salt thereof
and said second region comprising said naloxone or a
pharmaceutically acceptable salt thereof.
20. The composition of claim 11, wherein said buprenorphine or a
pharmaceutically acceptable salt thereof has a local pH of about 3
to about 9.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. patent
application Ser. No. 14/196,082, filed Mar. 4, 2014, which is a
Continuation of U.S. patent application Ser. No. 13/842,543, filed
Mar. 15, 2013, the entire contents of both of which are
incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to compositions, methods of
manufacture, products and methods of use relating to films
containing therapeutic actives. The invention more particularly
relates to self-supporting dosage forms which provide an agonist
acting alone or in combination with a buffer system to maximize
therapeutic absorption of the agonist. Some embodiments also
include an antagonist, with the buffer system acting to minimize
the absorption of the antagonist. Such compositions are
particularly useful for preventing misuse of the active while
providing sufficient buccal adhesion of the dosage form.
BACKGROUND OF THE RELATED TECHNOLOGY
[0003] Oral administration of two therapeutic actives in a single
dosage form can be complex if the intention is to have one active
absorbed into the body and the other active remain substantially
unabsorbed. For example, one active may be relatively soluble in
the mouth at one pH, and the other active may be relatively
insoluble at the same pH. Moreover, the absorption kinetics of each
therapeutic agent may be substantially different due to differing
absorption of the charged and uncharged species. These factors
represent some of the challenges in appropriately co-administering
therapeutic agents.
[0004] Co-administration of therapeutic agents has many
applications. Among such areas of treatment include treating
individuals who suffer from pain or other medical condition. Such
individuals may have a tendency to suffer from serious physical
dependence on the therapeutic agent, resulting in potentially
dangerous withdrawal effects when the therapeutic agent is not
administered to the individual. In order to provide treatment to
patients, it is known to provide a reduced level of a therapeutic
agent, which provides an effect of treating the condition, but does
not provide the "high" that may be provided by the therapeutic
agent. The drug provided may be an agonist or a partial agonist,
which may provide a reduction in pain or other symptom that the
patient is experiencing. However, even though these therapeutic
agents provide only a low level of euphoric effect, they are
capable of being abused by the individuals parenterally. In such
cases, it is desirable to provide a combination of the therapeutic
agent with a second therapeutic agent, which may decrease the
likelihood of diversion and abuse of the first drug. For example,
it is known to provide a dosage of an antagonist in combination
with the agonist or partial agonist. The narcotic antagonist binds
to a receptor in the brain to block the receptor, thus reducing the
effect of the agonist.
[0005] One such combination of narcotic agents has been marketed
under the trade name Suboxone.RTM. as an orally ingestible tablet.
However, such combinations in tablet form have the potential for
abuse. In some instances, the patient who has been provided the
drug may store the tablet in his mouth without swallowing the
tablet, then later extract the agonist from the tablet and inject
the drug into an individual's body. Although certain antagonists
(such as highly water-soluble antagonists) may be used to help
reduce the ability to separate the agonist, the potential for abuse
still exists. Further, incorporation of an antagonist in
combination with the pain-relieving agonist has been found to
reduce side effects associated with administration of the agonist,
such as constipation and other undesirable effects. It is desired
to provide a dosage that cannot be easily removed from the mouth
once it has been administered.
[0006] There is currently a need for an orally dissolvable film
dosage form that provides the desired absorption levels of the
agonist and antagonist, while providing an adhesive effect in the
mouth, rendering it difficult to remove once placed in the mouth
and achieving optimum absorption of the agonist while inhibiting
absorption of the antagonist.
SUMMARY OF THE INVENTION
[0007] In one embodiment of the present invention, there is
provided a self-supporting film dosage composition including: a
polymeric carrier matrix; a therapeutically effective amount of an
agonist or a pharmaceutically acceptable salt thereof; and a buffer
sufficient to maximize the absorption of the agonist.
[0008] In another embodiment of the present invention, there is
provided a self-supporting film dosage composition including a
polymeric carrier matrix, a therapeutically effective amount of an
agonist or a pharmaceutically acceptable salt thereof, a buffer
sufficient to maximize the absorption of the agonist, and a
chelator or antioxidant. In another embodiment of the present
invention, there is provided a self-supporting film dosage
composition including a polymeric carrier matrix, a therapeutically
effective amount of an agonist or a pharmaceutically acceptable
salt thereof, a therapeutically effective amount of an antagonist
or a pharmaceutically acceptable salt thereof, buffering system;
and a chelator or an antioxidant, wherein said buffering system
comprises a buffer capacity sufficient to inhibit the absorption of
said antagonist during the time which said composition is in the
oral cavity of a user.
[0009] In another embodiment of the present invention, there is
provided a self-supporting film dosage composition including: a
polymeric carrier matrix; a therapeutically effective amount of an
agonist or a pharmaceutically acceptable salt thereof; a
therapeutically effective amount of an antagonist or a
pharmaceutically acceptable salt thereof; and a buffering system;
where the buffering system possesses a buffer capacity sufficient
to inhibit the absorption of the antagonist during the time which
the composition is in the oral cavity of a user.
[0010] In still another embodiment of the present invention, there
is provided a method of treatment, including the steps of:
providing a film dosage composition including: a polymeric carrier
matrix; a therapeutically effective amount of an agonist or a
pharmaceutically acceptable salt thereof; and a buffer in an amount
sufficient to maximize the absorption of the agonist; and
administering the film dosage composition to a patient.
[0011] In other embodiments of the present invention, there is
provided a method of treatment, including the steps of: providing a
film dosage composition including: a polymeric carrier matrix; a
therapeutically effective amount of an agonist or a
pharmaceutically acceptable salt thereof; a therapeutically
effective amount of an antagonist or a pharmaceutically acceptable
salt thereof; a first buffer in an amount sufficient to obtain a
local pH of the agonist of about 4 to about 9; a buffer in an
amount sufficient to obtain a local pH of the antagonist of about 2
to about 4; and administering the film dosage composition to a
user.
[0012] In another embodiment of the present invention, there is
provided a self-supporting film dosage composition including: a
first region including: a first polymeric matrix; a therapeutically
effective amount of an agonist or a pharmaceutically acceptable
salt thereof; and a first buffering system in an amount sufficient
to optimize the absorption of the agonist; a second region
including: a second polymeric matrix; a therapeutically effective
amount of an antagonist; and a second buffering system in an amount
sufficient to inhibit the absorption of the antagonist.
[0013] In a further embodiment of the present invention, there is
provided an orally dissolving film formulation including a first
region including a therapeutically effective amount of an agonist
and second region including a therapeutically effective amount of
an antagonist, where the formulation provides an in vivo plasma
profile having a Cmax of about 0.868-6.94 ng/ml for the agonist and
an in vivo plasma profile having a Cmax of about 32.5-260 pg/ml for
the antagonist.
[0014] In another embodiment of the present invention, there is
provided a self-supporting film dosage composition including: a
polymeric carrier matrix; a therapeutically effective amount of an
agonist or a pharmaceutically acceptable salt thereof; a
therapeutically effective amount of an antagonist or a
pharmaceutically acceptable salt thereof; and a buffering system
sufficient to obtain a local pH of the antagonist of about 2 to
about 4.
[0015] In an embodiment of the present invention, there is provided
a self-supporting film dosage composition including: a polymeric
carrier matrix; a therapeutically effective amount of an agonist or
a pharmaceutically acceptable salt thereof; a therapeutically
effective amount of an antagonist or a pharmaceutically acceptable
salt thereof; and a buffering system sufficient to inhibit
absorption of the antagonist and optimize absorption of the agonist
when the film dosage composition is placed in the mouth of a
user.
[0016] In another embodiment of the present invention, there is
provided a self-supporting film dosage composition including: a
first region including: a first polymeric matrix; a therapeutically
effective amount of an agonist or a pharmaceutically acceptable
salt thereof; and a first buffering system in an amount sufficient
to optimize absorption of the agonist when the film dosage
composition is placed in the mouth of a user; and a second region
including: a second polymeric matrix; a therapeutically effective
amount of an antagonist; and a second buffering system in an amount
sufficient to inhibit absorption of the antagonist when the film
dosage composition is placed in the mouth of a user.
[0017] In yet another embodiment of the present invention, there is
provided a process of forming a film dosage composition including
the steps of: casting a film-forming composition, the film-forming
composition including: a polymeric carrier matrix; a
therapeutically effective amount of an agonist or a
pharmaceutically acceptable salt thereof; a therapeutically
effective amount of an antagonist or a pharmaceutically acceptable
salt thereof; and a buffer in an amount sufficient to optimize
absorption of the agonist and sufficient to inhibit absorption of
the antagonist when the film dosage composition is placed in the
mouth of a user; and drying the film-forming composition to form a
self-supporting film dosage composition.
[0018] In still another embodiment of the present invention, there
is provided a method of treatment, including the steps of:
providing a film dosage composition including: a polymeric carrier
matrix; a therapeutically effective amount of an agonist or a
pharmaceutically acceptable salt thereof; a therapeutically
effective amount of an antagonist or a pharmaceutically acceptable
salt thereof; and a buffering system in an amount sufficient to
provide an in vivo plasma profile having a Cmax of about
0.624-5.638 ng/ml for the agonist and an in vivo plasma profile
having a Cmax of less than 324 pg/ml for the antagonist; and
administering the film dosage composition to a user.
[0019] In another embodiment of the present invention, there is
provided a self-supporting film dosage composition including: a
first region including: a first polymeric matrix; a therapeutically
effective amount of an agonist or a pharmaceutically acceptable
salt thereof; and a first buffering system in an amount sufficient
to optimize the absorption of the agonist; a second region
including: a second polymeric matrix; a therapeutically effective
amount of an antagonist; and a second buffering system in an amount
sufficient to inhibit the absorption of the antagonist; where the
second region dissolves at a faster rate when placed in the oral
cavity of the user than the first region.
[0020] In another embodiment of the invention, there is provided a
process of forming a film dosage composition including the steps
of: casting a first film-forming composition, the first
film-forming composition including: a polymeric carrier matrix; a
therapeutically effective amount of an agonist or a
pharmaceutically acceptable salt thereof; and a buffer in an amount
sufficient to optimize absorption of the agonist when the film
dosage composition is placed in the mouth of a user; casting a
second film-forming composition, the second film-forming
composition including: a polymeric carrier matrix; a
therapeutically effective amount of an antagonist or a
pharmaceutically acceptable salt thereof; and a buffer in an amount
sufficient to inhibit absorption of the antagonist when the film
dosage composition is placed in the mouth of a user; and laminating
the first film-forming composition and the second film-forming
composition together to form a self-supporting film dosage
composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 shows a graph presenting the results of an EDTA
concentration study.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
[0022] As used herein, the term Cmax refers to the mean maximum
plasma concentration after administration of the composition to a
human subject. As also used herein, the term AUC refers to the mean
area under the plasma concentration-time curve value after
administration of the compositions formed herein. As will be set
forth in more detail below, the term "optimizing the absorption"
does not necessarily refer to reaching the maximum absorption of
the composition, and rather refers to reaching the optimum level of
absorption at a given pH. The "optimum" absorption may be, for
example, a level that provides a bioequivalent absorption as
administration of the currently available Suboxone.RTM. tablet.
Thus, if a bioequivalent absorption to Suboxone.RTM. is desired,
the Cmax of buprenorphine may be about 0.67 to about 5.36 ng/ml at
dosages of from 2-16 mg buprenorphine at a given pH. Similarly, an
"optimum" AUC of buprenorphine may be about 7.43 to about 59.46
hr*ng/ml at dosages of from 2-16 mg buprenorphine at a given pH. As
will be described in more detail below, it has been surprisingly
discovered that the absorption of one particular agonist,
buprenorphine, can provide an optimum absorption at a local pH of
about 3-4 as well as about 5.5-6.5. Thus, one may "optimize" the
absorption of buprenorphine by providing a local pH of about 3-4 or
about 5.5-6.5.
[0023] "Maximizing the absorption" refers to the maximum in vivo
absorption values achieved at a local pH of about 4 to about 9.
[0024] The term "local pH" refers to the local pH of the region of
the carrier matrix immediately surrounding the active agent as the
matrix hydrates and/or dissolves, for example, in the mouth of the
user.
[0025] By "inhibiting" the absorption of an active, it is meant
achieving as complete an ionization state of the active as
possible, such that little to none of the active is measurably
absorbable. For example, at a local pH of 3-3.5, the Cmax of an
active such as naloxone for dosage of 0.5 mg to 4.0 mg ranges from
32.5 to 260 pg/ml, and an AUC of naloxone for dosage of 0.5 mg to
4.0 mg ranges from 90.55 to 724.4 hr*pg/ml. It is understood that
at a local pH lower than 3.0, further ionization would be expected
and thus result in lower absorption.
[0026] The term "bioequivalent" means obtaining 80% to 125% of the
Cmax and AUC values for a given active in a different product. For
example, assuming Cmax and AUC values of buprenorphine for a
commercially-available Suboxone.RTM. tablet (containing 2 mg
buprenorphine and 0.5 mg naloxone) are 0.780 ng/ml and 6.789
hr*ng/ml, respectively, a bioequivalent product would have a Cmax
of buprenorphine in the range of 0.624-0.975 ng/ml, and an AUC
value of buprenorphine of 5.431-8.486 hr*ng/ml.
[0027] It will be understood that the term "film" includes thin
films, sheets and wafers, in any shape, including rectangular,
square, or other desired shape. The films described herein may be
any desired thickness and size such that it may be placed into the
oral cavity of the user. For example, the films may have a
relatively thin thickness of from about 0.1 to about 10 mils, or
they may have a somewhat thicker thickness of from about 10 to
about 30 mils. For some films, the thickness may be even larger,
i.e., greater than about 30 mils. Films may be in a single layer or
they may be multi-layered, including laminated films.
[0028] Oral dissolving films generally fall into three main
classes: fast dissolving, moderate dissolving and slow dissolving.
Fast dissolving films generally dissolve in about 1 second to about
30 seconds in the mouth. Moderate dissolving films generally
dissolve in about 1 to about 30 minutes in the mouth, and slow
dissolving films generally dissolve in more than 30 minutes in the
mouth. Fast dissolving films may consist of low molecular weight
hydrophilic polymers (i.e., polymers having a molecular weight
between about 1,000 to 9,000, or polymers having a molecular weight
below 200,000). In contrast, slow dissolving films generally have
high molecular weight polymers (i.e., having a molecular weight in
the millions).
[0029] Moderate dissolving films tend to fall in between the fast
and slow dissolving films. Moderate dissolving films dissolve
rather quickly, but also have a good level of mucoadhesion.
Moderate dissolving films are also flexible, quickly wettable, and
are typically non-irritating to the user. For the instant
invention, it is preferable to use films that fall between the
categories of fast dissolving and moderate dissolving. Such
moderate dissolving films provide a quick enough dissolution rate,
most desirably between about 1 minute and about 20 minutes, while
providing an acceptable mucoadhesion level such that the film is
not easily removable once it is placed in the oral cavity of the
user.
[0030] Inventive films described herein may include one or more
agonists or partial agonists. As used herein, the term "agonist"
refers to a chemical substance that is capable of providing a
physiological response or activity in the body of the user. The
films described herein may further include one or more antagonists.
As used herein, the term "antagonist" refers to any chemical
substance that acts within the body of the user to reduce the
physiological activity of another chemical substance. In some
embodiments, an antagonist used herein may act to reduce and/or
block the physiological activity of the agonist. The actives may be
water-soluble, or they may be water-insoluble. As used herein, the
term "water-soluble" refers to substances that are at least
partially dissolvable in a solvent, including but not limited to
water. The term "water-soluble" does not necessarily mean that the
substance is 100% dissolvable in the solvent. The term
"water-insoluble" refers to substances that are not readily
dissolvable in a solvent, including but not limited to water.
Solvents may include water, or alternatively may include other
polar solvents by themselves or in combination with water.
Inventive Films
[0031] The present invention relates to methods of treating pain or
other symptoms in an individual while limiting the potential for
abuse of the treatment. More desirably, the invention relates to
the treatment of physical pain in an individual, for example by
administration of an analgesic or other pain-relieving therapeutic
agent. One such therapeutic agent that is known to treat pain in
individuals includes an agonist such as buprenorphine. However,
buprenorphine is known to be a partial agonist and therefore can be
abused, and as such it is desired to combine buprenorphine with an
antagonist, thereby lessening the potential for abuse by parenteral
injection. Such combination of drugs is currently provided via a
product marketed under the trade name Suboxone.RTM., which is an
orally dissolvable tablet. This tablet which provides a combination
of buprenorphine (an opioid agonist) and naloxone (an opioid
antagonist). However, even using an antagonist such as naloxone may
be abused by a user. Therefore, the present invention provides a
method of treating pain or other symptoms in a patient by providing
an orally dissolvable film dosage, which provides a bioequivalent
effect to Suboxone.RTM.. The film dosage further preferably
provides buccal adhesion while it is in the user's mouth, rendering
it difficult to remove after placement.
[0032] The film dosage composition preferably includes a polymeric
carrier matrix. Any desired polymeric carrier matrix may be used,
provided that it is orally dissolvable. Desirably, the dosage
should have enough bioadhesion to not be easily removed and it
should form a gel like structure when administered. The orally
consumable films are preferably moderate-dissolving in the oral
cavity and particularly suitable for delivery of actives, although
both fast and sustained release compositions are also among the
various embodiments contemplated. In some embodiments, as will be
described in more detail below, the inventive combination may
include films that have more than one region, where each region has
a different dissolution profile.
[0033] The films used in the pharmaceutical products may be
produced by a combination of at least one polymer and a solvent,
optionally including other fillers known in the art. The solvent
may be water, a polar organic solvent including, but not limited
to, ethanol, isopropanol, acetone, or any combination thereof. In
some embodiments, the solvent may be a non-polar organic solvent,
such as methylene chloride. The film may be prepared by utilizing a
selected casting or deposition method and a controlled drying
process. For example, the film may be prepared through controlled
drying processes, which include application of heat and/or
radiation energy to the wet film matrix to form a visco-elastic
structure, thereby controlling the uniformity of content of the
film. Such processes are described in more detail in commonly
assigned U.S. Pat. No. 7,425,292, the contents of which are
incorporated herein by reference in their entirety. Alternatively,
the films may be extruded as described in commonly assigned U.S.
application Ser. No. 10/856,176, filed on May 28, 2004, and
published as U.S. Patent Publication No. 2005/0037055 A1, the
contents of which are incorporated herein by reference in their
entirety.
[0034] The polymer included in the films may be water-soluble,
water-swellable, water-insoluble, or a combination of one or more
either water-soluble, water-swellable or water-insoluble polymers.
The polymer may include cellulose or a cellulose derivative.
Specific examples of useful water-soluble polymers include, but are
not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl
cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol,
sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum,
guar gum, acacia gum, arabic gum, polyacrylic acid,
methylmethacrylate copolymer, carboxyvinyl copolymers, starch,
gelatin, and combinations thereof. Specific examples of useful
water-insoluble polymers include, but are not limited to, ethyl
cellulose, hydroxypropyl ethyl cellulose, cellulose acetate
phthalate, hydroxypropyl methyl cellulose phthalate and
combinations thereof. For higher dosages, it may be desirable to
incorporate a polymer which provides a high level of viscosity as
compared to polymers suitable for lower dosages.
[0035] As used herein the phrase "water-soluble polymer" and
variants thereof refer to a polymer that is at least partially
soluble in water, and desirably fully or predominantly soluble in
water, or absorbs water. Polymers that absorb water are often
referred to as being water-swellable polymers. The materials useful
with the present invention may be water-soluble or water-swellable
at room temperature and other temperatures, such as temperatures
exceeding room temperature. Moreover, the materials may be
water-soluble or water-swellable at pressures less than atmospheric
pressure. Desirably, the water-soluble polymers are water-soluble
or water-swellable having at least 20 percent by weight water
uptake. Water-swellable polymers having a 25 or greater percent by
weight water uptake are also useful. In some embodiments, films
formed from such water-soluble polymers may be sufficiently
water-soluble to be dissolvable upon contact with bodily
fluids.
[0036] Other polymers useful for incorporation into the films
include biodegradable polymers, copolymers, block polymers and
combinations thereof. It is understood that the term
"biodegradable" is intended to include materials that chemically
degrade in the presence of a solvent, as opposed to materials that
physically break apart (i.e., bioerodable materials). Among the
known useful polymers or polymer classes which meet the above
criteria are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA),
polydioxanes, polyoxalates, poly(.alpha.-esters), polyanhydrides,
polyacetates, polycaprolactones, poly(orthoesters), polyamino
acids, polyaminocarbonates, polyurethanes, polycarbonates,
polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers
thereof. Additional useful polymers include, stereopolymers of L-
and D-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid
and sebacic acid, sebacic acid copolymers, copolymers of
caprolactone, poly(lactic acid)/poly(glycolic
acid)/polyethyleneglycol copolymers, copolymers of polyurethane and
(poly(lactic acid), copolymers of polyurethane and poly(lactic
acid), copolymers of .alpha.-amino acids, copolymers of
.alpha.-amino acids and caproic acid, copolymers of .alpha.-benzyl
glutamate and polyethylene glycol, copolymers of succinate and
poly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixtures
thereof. Binary and ternary systems are contemplated.
[0037] Other specific polymers useful include those marketed under
the Medisorb and Biodel trademarks. The Medisorb materials are
marketed by the Dupont Company of Wilmington, Del. and are
generically identified as a "lactide/glycolide co-polymer"
containing "propanoic acid, 2-hydroxy-polymer with hydroxy-polymer
with hydroxyacetic acid." Four such polymers include
lactide/glycolide 100L, believed to be 100% lactide having a
melting point within the range of 338.degree.-347.degree. F.
(170.degree.-175.degree. C.); lactide/glycolide 100L, believed to
be 100% glycolide having a melting point within the range of
437.degree.-455.degree. F. (225.degree.-235.degree. C.);
lactide/glycolide 85/15, believed to be 85% lactide and 15%
glycolide with a melting point within the range of
338.degree.-347.degree. F. (170.degree.-175.degree. C.); and
lactide/glycolide 50/50, believed to be a copolymer of 50% lactide
and 50% glycolide with a melting point within the range of
338.degree.-347.degree. F. (170.degree.-175.degree. C.).
[0038] The Biodel materials represent a family of various
polyanhydrides which differ chemically.
[0039] Although a variety of different polymers may be used, it is
desired to select polymers that provide mucoadhesive properties to
the film, as well as a desired dissolution and/or disintegration
rate. In particular, the time period for which it is desired to
maintain the film in contact with the mucosal tissue depends on the
type of active contained in the composition. Some actives may only
require a few minutes for delivery through the mucosal tissue,
whereas other actives may require up to several hours or even
longer. Accordingly, in some embodiments, one or more water-soluble
polymers, as described above, may be used to form the film. In
other embodiments, however, it may be desirable to use combinations
of water-soluble polymers and polymers that are water-swellable,
water-insoluble and/or biodegradable, as provided above. The
inclusion of one or more polymers that are water-swellable,
water-insoluble and/or biodegradable may provide films with slower
dissolution or disintegration rates than films formed from
water-soluble polymers alone. As such, the film may adhere to the
mucosal tissue for longer periods or time, such as up to several
hours, which may be desirable for delivery of certain active
components.
[0040] Desirably, the individual film dosage has a small size that
is between about 0.5-1 inch by about 0.5-1 inch. Most preferably,
the film dosage is about 0.75 inches.times.0.5 inches. The film
dosage should have good adhesion when placed in the buccal cavity
or in the sublingual region of the user. Further, the film dosage
should disperse and dissolve at a moderate rate, that is, between
about 1 minute to about 30 minutes, and most desirably between
about 10 minutes and about 20 minutes. In some embodiments,
however, it may be desired to allow the individual film dosage to
dissolve slower, over a period of longer than about 30 minutes. In
such slow dissolving embodiments, it is preferable that the film
dosage has strong mucoadhesion properties. In other embodiments,
however, it may be desirable to use a faster dissolving material,
for example between about 1 to about 3 minutes. Further, the film
dosage should include components that aid in adhesion to the inner
surface of the user's oral cavity, such as the buccal cavity or
sublingually. In particular, for dual-layered films, the region
including the agonist should have a higher degree of adhesion than
the region including the antagonist. In this fashion, the agonist
may be released quicker and ingested by the user.
[0041] For instance, in some embodiments, the films may include
polyethylene oxide alone or in combination with a second polymer
component. In some embodiments, the films may include polymers
other than polyethylene oxide. The second polymer may be another
water-soluble polymer, a water-swellable polymer, a water-insoluble
polymer, a biodegradable polymer or any combination thereof.
Suitable water-soluble polymers include, without limitation, any of
those provided above. In some embodiments, the water-soluble
polymer may include hydrophilic cellulosic polymers, such as
hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose. Other
specific examples of useful water soluble polymers include, but are
not limited to, polyethylene oxide (PEO), pullulan, hydroxypropyl
cellulose, polydextrose, polyvinyl pyrrolidone, carboxymethyl
cellulose, polyvinyl alcohol, sodium alginate, propylene glycol
alginate, carrageenan, polyethylene glycol, xanthan gum,
tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic
acid, methylmethacrylate copolymer, poloxamer polymers, copolymers
of acrylic acid and alkyl acrylate (availale as Pemulen.RTM.
polymers), carboxyvinyl copolymers, starch, gelatin, pectin, and
combinations thereof.
[0042] Specific examples of useful water insoluble polymers
include, but are not limited to, ethyl cellulose, hydroxypropyl
ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl
cellulose phthalate, acrylic polymers, vinyl acetate, sodium
sulphonated polyesters, carboxylated acrylics,
trimethylpentanediol/adipic acid/glycerin cross polymer,
polyglycerol-2-diisostearate/IPDI copolymer, carboxylated vinyl
acetate copolymer, vinylpyrrolicone/vinyl
acetate/alkylaminoacrylate terpolymers, vinylpyrrolidone/vinyl
acetate copolymer, and combinations thereof.
[0043] In accordance with some embodiments, polyethylene oxide may
range from about 20% to 100% by weight in the polymer component,
more specifically about 30% to about 70% by weight, and even more
specifically about 40% to about 60% by weight. In some embodiments,
one or more water-swellable, water-insoluble and/or biodegradable
polymers also may be included in the polyethylene oxide-based film.
Any of the water-swellable, water-insoluble or biodegradable
polymers provided above may be employed. The second polymer
component may be employed in amounts of about 0% to about 80% by
weight in the polymer component, more specifically about 30% to
about 70% by weight, and even more specifically about 40% to about
60% by weight.
[0044] The molecular weight of the polyethylene oxide also may be
varied. In some embodiments, high molecular weight polyethylene
oxide, such as about 4 million, may be desired to increase
mucoadhesivity of the film. In some other embodiments, the
molecular weight may range from about 100,000 to 900,000, more
specifically from about 100,000 to 600,000, and even more
specifically from about 100,000 to 300,000. In some embodiments, it
may be desirable to combine high molecular weight (600,000 to
900,000) with low molecular weight (100,000 to 300,000)
polyethylene oxide in the polymer component. Suitable polymers
include those described in the applicant's co-pending application,
U.S. Publication Number 2008-0260809, the entire contents of which
are incorporated by reference herein.
[0045] A variety of optional components and fillers also may be
added to the films. These may include, without limitation:
surfactants; plasticizers; polyalcohols; anti-foaming agents, such
as silicone-containing compounds, which promote a smoother film
surface by releasing oxygen from the film; thermo-setting gels such
as pectin, carageenan, and gelatin, which help in maintaining the
dispersion of components; inclusion compounds, such as
cyclodextrins and caged molecules; coloring agents; and flavors. In
some embodiments, more than one active component may be included in
the film.
[0046] Chelators may be included in the films. Applicants have
surprisingly discovered that chelators may be employed to reduce or
eliminate the oxidation of active ingredients in film compositions.
In fact, chelators can be as effective as or even more effective
than anti-oxidants in preventing or reducing oxidation of some
actives, such as naloxone.
[0047] In practice, a chelator is added to the compositions of the
present invention in the same manner as any other additive. In
certain embodiments, a chelator is added to one or more regions of
a multi-region film. In another embodiment, a chelator is added to
one or both regions of a dual region film. In these embodiments,
the chelator may be the same in each region or may differ between
regions.
[0048] The chelator may be any chelator known in the art. Chelators
have two functional groups that donate a pair of electrons such as
.dbd.O, --NH2, --COO-- and allow ring formation with metal.
Examples of chelators include, for example,
ethylenediaminetetraacetic acid (EDTA), proteins, polysaccharides,
polynucleic acids, glutamic acid, histidine, organic diacids,
polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid,
phosphonates, transferrin, desferrioxamine, and combinations
thereof. Preferably, the chelator is EDTA or a salt thereof. Salts
of EDTA include, for example, EDTA disodium salt, EDTA
tetraammonium salt, EDTA tetrasodium salt, EDTA calcium disodium
salt, EDTA tetrapotassium salt, EDTA diammonium salt.
[0049] In an embodiment of the present invention, the chelator is
present in the film dosage compositions in an amount of about 0.1
to about 10% by weight of the total film dosage composition,
preferably in an amount of 0.5 to about 7.5%, and more preferable
in an amount of about 1 to about 2%.
[0050] In an embodiment of the present invention, the weight ratio
of antagonist, such as naloxone, to chelator of about 0.2 to 2 to
about 2 to 0.5, preferably in a weight ratio of 1 to 2 about 2 to
1.
[0051] Antioxidants may be included in the films. Antioxidants may
be included in the films. Examples of such antioxidants include
phenol antioxidants such as dibutylhydroxytoluene (BHT) IUPAC name:
2,6-bis(1,1-dimethylethyl)-4-methylphenol) and dibutylated
hydroxyanisole (BHA); propyl gallate, sodium sulfate, citric acid,
sodium metabusulfite, ascorbic acid, tocopherol, tocopherol ester
derivatives, 2-mercaptobenzimidazole and the like. Among these
antioxidants, preferred are ascorbic acid, dibutylhydroxytoluene
(BHT), propyl gallate, sodium sulfite, citric acid, sodium
metabisulfite, and combinations thereof. The amount of an
antioxidant to be used is preferably 0.1 to 20% by mass and more
preferably 0.5 to 10% by mass per the total mass of the film dosage
composition.
[0052] In an embodiment of the present invention, the film dosage
composition either a chelator or an antioxidant. In another
embodiment, the film dosage composition includes both a chelator
and an antioxidant.
[0053] Additives may be included in the films. Examples of classes
of additives include excipients, lubricants, buffering agents,
stabilizers, blowing agents, pigments, coloring agents, fillers,
bulking agents, sweetening agents, flavoring agents, fragrances,
release modifiers, adjuvants, plasticizers, flow accelerators, mold
release agents, polyols, granulating agents, diluents, binders,
buffers, absorbents, glidants, adhesives, anti-adherents,
acidulants, softeners, resins, demulcents, solvents, surfactants,
emulsifiers, elastomers and mixtures thereof. These additives may
be added with the active ingredient(s).
[0054] Useful additives include, for example, gelatin, vegetable
proteins such as sunflower protein, soybean proteins, cotton seed
proteins, peanut proteins, grape seed proteins, whey proteins, whey
protein isolates, blood proteins, egg proteins, acrylated proteins,
water-soluble polysaccharides such as alginates, carrageenans, guar
gum, agar-agar, xanthan gum, gellan gum, gum arabic and related
gums (gum ghatti, gum karaya, gum tragancanth), pectin,
water-soluble derivatives of cellulose: alkylcelluloses
hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as
methylcelulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxyethylmethylcellulose,
hydroxypropylmethylcellulose, hydroxybutylmethylcellulose,
cellulose esters and hydroxyalkylcellulose esters such as cellulose
acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC);
carboxyalkylcelluloses, carboxyalkylalkylcelluloses,
carboxyalkylcellulose esters such as carboxymethylcellulose and
their alkali metal salts; water-soluble synthetic polymers such as
polyacrylic acids and polyacrylic acid esters, polymethacrylic
acids and polymethacrylic acid esters, polyvinylacetates,
polyvinylalcohols, polyvinylacetatephthalates (PVAP),
polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, and
polycrotonic acids; also suitable are phthalated gelatin, gelatin
succinate, crosslinked gelatin, shellac, water-soluble chemical
derivatives of starch, cationically modified acrylates and
methacrylates possessing, for example, a tertiary or quaternary
amino group, such as the diethylaminoethyl group, which may be
quaternized if desired; and other similar polymers.
[0055] Such extenders may optionally be added in any desired amount
desirably within the range of up to about 80%, desirably about 3%
to 50% and more desirably within the range of 3% to 20% based on
the weight of all film components.
[0056] Further additives may be flow agents and opacifiers, such as
the oxides of magnesium aluminum, silicon, titanium, etc. desirably
in a concentration range of about 0.02% to about 3% by weight and
desirably about 0.02% to about 1% based on the weight of all film
components.
[0057] Further examples of additives are plasticizers which include
polyalkylene oxides, such as polyethylene glycols, polypropylene
glycols, polyethylene-propylene glycols, organic plasticizers with
low molecular weights, such as glycerol, glycerol monoacetate,
diacetate or triacetate, triacetin, polysorbate, cetyl alcohol,
propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl
citrate, tributyl citrate, and the like, added in concentrations
ranging from about 0.5% to about 30%, and desirably ranging from
about 0.5% to about 20% based on the weight of the polymer.
[0058] There may further be added compounds to improve the texture
properties of the starch material such as animal or vegetable fats,
desirably in their hydrogenated form, especially those which are
solid at room temperature. These fats desirably have a melting
point of 50.degree. C. or higher. Preferred are tri-glycerides with
C.sub.12--, C.sub.14--, C.sub.16--, C.sub.18--, C.sub.20-- and
C.sub.22-- fatty acids. These fats can be added alone without
adding extenders or plasticizers and can be advantageously added
alone or together with mono- and/or di-glycerides or phosphatides,
especially lecithin. The mono- and di-glycerides are desirably
derived from the types of fats described above, i.e. with
C.sub.12--, C.sub.14--, C.sub.16--, C.sub.18--, C.sub.20-- and
C.sub.22-- fatty acids.
[0059] The total amounts used of the fats, mono-, di-glycerides
and/or lecithins may be up to about 5% and preferably within the
range of about 0.5% to about 2% by weight of the total film
composition.
[0060] It further may be useful to add silicon dioxide, calcium
silicate, or titanium dioxide in a concentration of about 0.02% to
about 1% by weight of the total composition. These compounds act as
flow agents and opacifiers.
[0061] Lecithin is one surface active agent for use in the films
described herein. Lecithin may be included in the feedstock in an
amount of from about 0.25% to about 2.00% by weight. Other surface
active agents, i.e. surfactants, include, but are not limited to,
cetyl alcohol, sodium lauryl sulfate, the Spans.TM. and Tweens.TM.
which are commercially available from ICI Americas, Inc.
Ethoxylated oils, including ethoxylated castor oils, such as
Cremophor.RTM. EL which is commercially available from BASF, are
also useful. Carbowax.TM. is yet another modifier which is very
useful in the present invention. Tweens.TM. or combinations of
surface active agents may be used to achieve the desired
hydrophilic-lipophilic balance ("HLB").
[0062] Other ingredients include binders which contribute to the
ease of formation and general quality of the films. Non-limiting
examples of binders include starches, pregelatinize starches,
gelatin, polyvinylpyrrolidone, methylcellulose, sodium
carboxymethylcellulose, ethylcellulose, polyacrylamides,
polyvinyloxoazolidone, and polyvinylalcohols. If desired, the film
may include other additives, such as keratin, or proteins,
including proteins that are useful in forming a gel, such as
gelatine.
[0063] Further potential additives include solubility enhancing
agents, such as substances that form inclusion compounds with
active components. Such agents may be useful in improving the
properties of very insoluble and/or unstable actives. In general,
these substances are doughnut-shaped molecules with hydrophobic
internal cavities and hydrophilic exteriors. Insoluble and/or
instable actives may fit within the hydrophobic cavity, thereby
producing an inclusion complex, which is soluble in water.
Accordingly, the formation of the inclusion complex permits very
insoluble and/or instable actives to be dissolved in water. A
particularly desirable example of such agents are cyclodextrins,
which are cyclic carbohydrates derived from starch. Other similar
substances, however, are considered well within the scope of the
present invention.
[0064] Suitable coloring agents include food, drug and cosmetic
colors (FD&C), drug and cosmetic colors (D&C), or external
drug and cosmetic colors (Ext. D&C). These colors are dyes,
their corresponding lakes, and certain natural and derived
colorants. Lakes are dyes absorbed on aluminum hydroxide.
[0065] Other examples of coloring agents include known azo dyes,
organic or inorganic pigments, or coloring agents of natural
origin. Inorganic pigments are preferred, such as the oxides or
iron or titanium, these oxides, being added in concentrations
ranging from about 0.001 to about 10%, and preferably about 0.5 to
about 3%, based on the weight of all the components.
[0066] Flavors may be chosen from natural and synthetic flavoring
liquids. An illustrative list of such agents includes volatile
oils, synthetic flavor oils, flavoring aromatics, oils, liquids,
oleo resins or extracts derived from plants, leaves, flowers,
fruits, stems and combinations thereof. A non-limiting
representative list of examples includes mint oils, cocoa, and
citrus oils such as lemon, orange, grape, lime and grapefruit and
fruit essences including apple, pear, peach, grape, strawberry,
raspberry, cherry, plum, pineapple, apricot or other fruit
flavors.
[0067] Other useful flavorings include aldehydes and esters such as
benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon,
lime), neral, i.e., beta-citral (lemon, lime), decanal (orange,
lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits),
aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond),
2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus,
mandarin), combinations thereof and the like.
[0068] The sweeteners may be chosen from the following non-limiting
list: glucose (corn syrup), dextrose, invert sugar, fructose, and
combinations thereof; saccharin and its various salts such as the
sodium salt; dipeptide sweeteners such as aspartame;
dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana
(Stevioside); chloro derivatives of sucrose such as sucralose;
sugar alcohols such as sorbitol, mannitol, xylitol, and the like.
Also contemplated are hydrogenated starch hydrolysates and the
synthetic sweetener
3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,
particularly the potassium salt (acesulfame-K), and sodium and
calcium salts thereof, and natural intensive sweeteners, such as Lo
Han Kuo. Other sweeteners may also be used.
[0069] The films may include one or more additives to provide a
taste masking of the active component. For example, the films may
include ionic exchange resins, including but not limited to a
water-insoluble organic or inorganic matrix material having
covalently bound functional groups that are ionic or capable of
being ionized under appropriate conditions. The organic matrix may
be synthetic (e.g., polymers or copolymers or acrylic acid,
methacrylic acid, sulfonated styrene or sulfonated divinylbenzene)
or partially synthetic (e.g., modified cellulose or dextrans). The
inorganic matrix may be, for example, silica gel modified by the
addition of ionic groups. Most ion exchange resins are cross-linked
by a crosslinking agent, such as divinylbenzene.
[0070] Anti-foaming and/or de-foaming components may also be used
with the films. These components aid in the removal of air, such as
entrapped air, from the film-forming compositions. Such entrapped
air may lead to non-uniform films. Simethicone is one particularly
useful anti-foaming and/or de-foaming agent. The present invention,
however, is not so limited and other anti-foam and/or de-foaming
agents may suitable be used.
[0071] As a related matter, simethicone and related agents may be
employed for densification purposes. More specifically, such agents
may facilitate the removal of voids, air, moisture, and similar
undesired components, thereby providing denser, and thus more
uniform films. Agents or components which perform this function can
be referred to as densification or densifying agents. As described
above, entrapped air or undesired components may lead to
non-uniform films.
[0072] Simethicone is generally used in the medical field as a
treatment for gas or colic in babies. Simethicone is a mixture of
fully methylated linear siloxane polymers containing repeating
units of polydimethylsiloxane which is stabilized with
trimethylsiloxy end-blocking unites, and silicon dioxide. It
usually contains 90.5-99% polymethylsiloxane and 4-7% silicon
dioxide. The mixture is a gray, translucent, viscous fluid which is
insoluble in water.
[0073] When dispersed in water, simethicone will spread across the
surface, forming a thin film of low surface tension. In this way,
simethicone reduces the surface tension of bubbles air located in
the solution, such as foam bubbles, causing their collapse. The
function of simethicone mimics the dual action of oil and alcohol
in water. For example, in an oily solution any trapped air bubbles
will ascend to the surface and dissipate more quickly and easily,
because an oily liquid has a lighter density compared to a water
solution. On the other hand, an alcohol/water mixture is known to
lower water density as well as lower the water's surface tension.
So, any air bubbles trapped inside this mixture solution will also
be easily dissipated. Simethicone solution provides both of these
advantages. It lowers the surface energy of any air bubbles that
trapped inside the aqueous solution, as well as lowering the
surface tension of the aqueous solution. As the result of this
unique functionality, simethicone has an excellent anti-foaming
property that can be used for physiological processes (anti-gas in
stomach) as well as any for external processes that require the
removal of air bubbles from a product.
[0074] In order to prevent the formation of air bubbles in the
films, the mixing step may be performed under vacuum. However, as
soon as the mixing step is completed, and the film solution is
returned to the normal atmosphere condition, air will be
re-introduced into or contacted with the mixture. In many cases,
tiny air bubbles will be again trapped inside this polymeric
viscous solution. The incorporation of simethicone into the
film-forming composition either substantially reduces or eliminates
the formation of air bubbles during and after mixing.
[0075] Simethicone may be added to the film-forming mixture as an
anti-foaming agent in an amount from about 0.01 weight percent to
about 5.0 weight percent, more desirably from about 0. 05 weight
percent to about 2.5 weight percent, and most desirably from about
0. 1 weight percent to about 1.0 weight percent.
[0076] Any other optional components described in commonly assigned
U.S. Pat. No. 7,425,292 and U.S. application Ser. No. 10/856,176,
referred to above, also may be included in the films described
herein.
[0077] When the dosage form includes at least one antagonist in
addition to the agonist, it may be desired to control the release
of the antagonist, so as to minimize or wholly prevent the
absorption of the antagonist from the dosage form when taken
orally. In this fashion, the antagonist may be released faster and
a larger proportion of it may be present as the ionized form in
solution, thereby lessening the likelihood of its absorption in the
body. Desirably, the dosage form is a self-supporting film
composition, which is placed into the oral cavity of the user. In a
dosage form that is to be placed in the oral cavity, it is desired
to absorb the agonist buccally, so as to provide rapid absorption
of the agonist into the body of the user. At the same time, it may
be desired to inhibit or reduce absorption of any antagonist
buccally, thereby allowing the antagonist to be swallowed and
destroyed in the stomach, or in some cases absorbed in the colon.
Inhibiting the absorption of an antagonist may alternatively be
achieved via physical means, such as by encapsulating the
antagonist in a material that blocks absorption. It is desired,
however, to reduce the absorption of the antagonist by chemical
means, such as by controlling the local pH of the dosage form.
[0078] It has been found that by controlling the local pH of the
dosage form, the release and/or absorption of the actives therein
may be controlled. For example, in a dosage that includes an amount
of an agonist, the local pH may be controlled to a level that
optimizes its release and/or absorption into the oral cavity of the
user. In dosages incorporating an amount of an agonist and an
amount of an antagonist, the local pH may be controlled to a level
that maximizes the release and/or oral absorption of the agonist
while simultaneously minimizing the release and/or oral absorption
of the antagonist. For example, the film dosage may include
distinct regions, one region including an agonist and the other
region including an antagonist, where the local pH of each region
is optimized for the desired effect.
[0079] The dosage form preferably includes a combination of an
agonist and an antagonist, while the dosage has a controlled local
pH. It should be understood that the present invention is not
limited to the use of any one particular agonist and/or antagonist,
and any agonist (or partial agonist) and any antagonist may be
incorporated into the present invention. The agonist and optional
antagonist should be selected from those agonists and antagonists
that are useful in treating the particular symptom being treated.
The inventive films discussed herein are best suited for agonists
and/or antagonists that are basic in nature. Suitable agonists
(and/or partial agonists) may include buprenorphine (pKa=8.42),
sufentanil (pKa=8.0), morphine (pKa=8.0), fentanil (pKa=8.4),
alfentanil (pKa=6.5), pethidine (pKa=8.7), apomorphine (pKa=8.9),
alphaprodine (pKa=8.7), remifentanil (pKa=7.0), methadone
(pKa=9.2), codeine (pKa=8.2), dihydrocodeine (pKa=9.4), morphine
(pKa=8.0), oxycodone (pKa=8.53), oxymorphone (pKa=8.17), tramadol
(pKa=9.41), or pharmaceutically acceptable salts thereof. Suitable
antagonists (and/or partial antagonists) may include naloxone,
naltrexone, nalorphine and levallorphan, or therapeutically
acceptable salts thereof.
[0080] As discussed above, the local pH of the dosage is preferably
controlled to provide the desired release and/or absorption of the
agonist and antagonist. Suitable agonists may have a pKa of about 5
to about 9.5, and most preferably from about 8.0 to about 9.0.
Suitable antagonists may have a pKa of about 6.0 to about 9.0, and
most preferably about 7.0 to about 9.0. For example, naloxone has a
pKa of about 7.94.
[0081] According to pH partition theory, one would expect that
saliva (which has a local pH of about 6.5) would maximize the
absorption of both actives. As generally understood, absorption of
an active depends on the available unionized form of the active.
Thus, as the local pH of the surrounding environment is lowered,
basic actives will be more ionized, and less will be available for
absorption. For an active which has a pKa of about 8, one would
expect a higher level of absorption to occur at a local pH level of
about 6.5, whereas a lower level of absorption should occur at a
local pH of about 3.5, since most of the active would be ionized.
As will be described in more detail in the Examples below,
controlling the local pH of the film compositions of the present
invention provides a system in which the desired release and/or
absorption of the components is achieved.
[0082] In one embodiment, the dosage form is a self-supporting
film. In this embodiment, the film dosage includes a polymer
carrier matrix, a therapeutically effective amount of an agonist or
a pharmaceutically acceptable salt thereof, and a buffer.
Preferably, the agonist is a partial agonist, and most desirably
the agonist is an opioid agonist, such as buprenorphine. The buffer
is preferably capable of providing a local pH of the composition
within a range that provides a controllable level and desirably an
optimal treatment level of absorption of the agonist. For example,
it may be desired to provide an absorption of buprenorphine that is
bioequivalent to a Suboxone.RTM. tablet.
[0083] It has been surprisingly discovered by the Applicants that
certain agonists, such as buprenorphine, are capable of being
suitably absorbed when the local pH of the film composition is
either between about 3 to about 4 or between about 5 to about 9.
Thus, the local pH for the film including the agonist may be either
from about 3 to about 4 or from about 5 to about 9. To provide a
maximum absorption of buprenorphine, for example, the local pH of
the film composition may be about 5.5. To provide an absorption of
buprenorphine that is bioequivalent to the Suboxone.RTM. tablet,
the local pH of the film composition may be about 6 to about 7. The
resulting dosage is a film composition that allows for a rapid and
effective release of the agonist (such as buprenorphine) into the
oral cavity of the user. At the same time, the film composition
desirably has a sufficient adhesion profile, such that the film
cannot easily be removed, or cannot be removed at all, from the
oral cavity of the user once it has been placed into the cavity.
Full release of the agonist may take place within less than about
thirty minutes, e.g., within about 10 minutes to about 30 minutes
and preferably remains in the oral cavity for at least 1 minute and
desirably about 1 to about 30 minutes.
[0084] It may be desirable to combine the opioid agonist (or
partial agonist) in the film composition with an opioid antagonist
or a pharmaceutically acceptable salt thereof. The agonist and
antagonist may be dispersed throughout the dosage separately or the
agonist and antagonist may be separately dispersed in individual
film regions. Most desirably the antagonist includes naloxone, but
any suitable antagonist may be selected as desired. The antagonist
may optionally be water-soluble, so as to render separation of the
antagonist and agonist difficult, thereby lessening the potential
for diversion abuse of the agonist.
[0085] As with a film including an agonist, a film including an
agonist and an antagonist is desirably pH-controlled through the
inclusion of a buffer. At the desired local pH level of the agonist
and the antagonist, optimal absorption of the agonist may be
achieved while the absorption of the antagonist may be greatly
inhibited.
[0086] The film may contain any desired level of self-supporting
film forming polymer, such that a self-supporting film composition
is provided. In one embodiment, the film composition contains a
film forming polymer in an amount of at least 25% by weight of the
composition. The film forming polymer may alternatively be present
in an amount of at least 50% by weight of the composition, and
desirably in a range of about 25% to about 75%, and most desirably
from about 30% to about 50% by weight of the composition. As
explained above, any film forming polymers may be used as
desired.
[0087] Any desired level of agonist and optional antagonist may be
included in the dosage, so as to provide the desired therapeutic
effect. In one particular embodiment, the film composition includes
about 2 mg to about 16 mg of agonist per dosage. More desirably,
the film composition includes about 4 mg to about 12 mg of agonist
per dosage. If desired, the film composition may include about 0.5
mg to about 5 mg of antagonist per dosage. More desirably, the film
composition includes about 1 mg to about 3 mg of antagonist per
dosage. If an antagonist is incorporated into the film, the film
composition may include the antagonist in a ratio of about 6:1-2:1
agonist to antagonist. Most desirably, the film composition
contains about 4:1 agonist to antagonist per dosage. For example,
in one embodiment, the dosage includes an agonist in an amount of
about 12 mg, and includes an antagonist in an amount of about 3
mg.
[0088] The film compositions further desirably include at least one
buffer so as to control the local pH of the film composition. Any
desired level of buffer may be incorporated into the film
composition so as to provide the desired local pH level. The buffer
is preferably provided in an amount sufficient to control the
release from the film and/or the absorption into the body of the
agonist and the optional antagonist. In a desired embodiment, the
film composition includes buffer in a ratio of buffer to agonist in
an amount of from about 2:1 to about 1:5 (buffer:agonist). The
buffer may alternatively be provided in a 1:1 ratio of buffer to
agonist. A film composition including an antagonist preferably has
a local pH of about 2 to about 4. Any buffer may be used as
desired. In some embodiments, the buffer may include sodium
citrate, citric acid, succinic acid, malic acid, phosphoric acid,
boric acid, and combinations thereof. The buffer may include a
buffering system including a combination of components, such as
Citric Acid/Sodium Citrate, Succinic Acid/Monosodium Succinate,
Glycine/Sodium Glycine, Malic Acid/Sodium Malate, Phosphoric
Acid/Sodium Phosphate, Fumaric Acid/Sodium Fumarate, Monosodium
Phosphate/Disodium Phosphate, and Boric Acid/Sodium Borate.
[0089] In this embodiment, the resulting film composition includes
a polymer matrix, an agonist, and an optional antagonist, while the
film composition has a controlled local pH to the level desired.
The buffer is desirably present in an amount to provide a
therapeutically adequate absorption of the agonist, while
simultaneously limiting or preventing substantial absorption of the
antagonist. Controlling of the local pH allows for the desired
release and/or absorption of the components, and thus provides a
more useful and effective dosage.
[0090] The film dosage composition may include a polymer carrier
matrix, a therapeutically effective amount of agonist, a
therapeutically effective amount of antagonist, and a buffering
system. A "therapeutically effective amount" of an antagonist is
intended to refer to an amount of the antagonist that is useful in
diverting abuse of the agonist by a user. The buffering system may
include a buffer in addition to a solvent. The buffering system
desirably includes a sufficient level of buffer so as to provide a
desired local pH level of the film dosage composition.
[0091] In addition to a desired local pH level, the buffer
desirably has a buffer capacity sufficient to maintain ionization
of the optional antagonist during the time that the composition is
in the oral cavity of a user. Maintaining ionization of the
antagonist serves to limit the absorption of the antagonist, and
thus provide the desired control of the antagonist. While the
ionization of the antagonist is limited, the ionization of the
agonist may not be so limited. As such, the resulting dosage form
provides absorption of the agonist to the user, while sufficiently
reducing and/or preventing absorption of the antagonist.
[0092] In other embodiments, the film dosage composition of the
present invention may include an agonist in a sufficient amount so
as to provide a release profile bioequivalent to a tablet
containing a higher amount of the agonist. By providing a film
dosage composition with an agonist and simultaneously controlling
the local pH of the film dosage composition, an effective release
and absorption of the agonist may be achieved with less of the
agonist present in the dosage. For example, the film dosage
composition may include an agonist in an amount that is at least
1.5 times less than the amount of the agonist required in a tablet,
but still provides a bioequivalent release profile. In some
embodiments, the agonist may be a partial agonist. In some
embodiments the agonist may be an opioid agonist. In desired
embodiments, the agonist includes buprenorphine or a
pharmaceutically acceptable salt thereof.
[0093] The film dosage composition including an agonist, may be
configured to provide an in vivo plasma profile having a mean
maximum plasma concentration (Cmax) in a desired range. For
example, the desired Cmax may be a bioequivalent level to that of a
Suboxone.RTM. tablet. It has been discovered by the Applicants that
controlling the Cmax of the film composition allows one to control
the absorption of the active (such as an agonist) into the user.
The resulting film composition is more effective and suitable for
delivery to a user.
[0094] In one embodiment, the Cmax of the film composition may be
about 6.4 ng/ml or less. If desired, the Cmax of the film
composition may be less than about 5.2 ng/ml, less than about 3.8
ng/ml, less than about 1.9 ng/ml, or less than about 1.1 ng/ml,
depending on the desired dosage level. In such embodiments, the
agonist may be present in an amount of from about 2 mg to about 16
mg per dosage, or, if desired about 4 mg to about 12 mg per dosage.
The agonist may include buprenorphine or a pharmaceutically
acceptable salt thereof.
[0095] It has further been discovered that, by controlling the mean
area under the curve (AUC) value of the film composition, a more
effective dosage form may be provided. In one embodiment, the film
composition may include a mean AUC value of about 6.8 hrng/ml or
greater. Alternatively, the film composition may include a mean
AUCinf value of from about 6.8 hrng/ml to about 66 hrng/ml.
[0096] As explained above, the film compositions may include an
optional antagonist. When the film composition includes a
combination of agonist and antagonist, the film composition may be
configured to provide a particular Cmax and/or AUC for the
antagonist. For example, when a buprenorphine agonist and a
naloxone antagonist are incorporated into the film composition, the
naloxone may be configured to provide a Cmax of less than about 400
pg/ml, less than about 318 pg/ml, less than about 235 pg/ml, less
than about 92 pg/ml or less than about 64 pg/ml. In such films, the
naloxone may provide a mean AUC value of less than about 1030
hrng/ml.
[0097] In formulations which include an agonist in combination with
an antagonist, the film composition may be prepared to provide a
desired Cmax and/or AUC value for each of the agonist and
antagonist. For example, a dosage having 16 mg of agonist and 4 mg
of antagonist may provide an in vivo plasma profile having a Cmax
of less than about 6.4 ng/ml for the agonist and an in vivo plasma
profile having a Cmax of less than about 400 pg/ml for the
antagonist. Such formulation may also provide an AUC value of more
than about 6.8 hrng/ml for the agonist. If desired, the formulation
may provide an AUCinf value of less than about 1030 hrpg/ml for the
antagonist. Bioequivalence levels are set forth in more detail in
the Examples discussed below. Such compositions may include the
agonist and the antagonist in any desired amount, and in a
preferred embodiment, the composition includes about 2 mg to about
16 mg of the agonist per dosage and about 0.5 mg to about 4 mg of
the antagonist per dosage. Most desirably, the agonist and
antagonist are present in amounts of about 4:1 by weight agonist to
antagonist.
[0098] In one particular embodiment, there may be provided a
self-supporting film dosage composition including more than one
region (referred to as a "dual-film product" or a "dual-region
product"). The multiple regions may be disposed on top of each
other, to the side of each other, or disposed internally of each
other. For example, the dosage composition may include two separate
regions, disposed in such a configuration where the first region is
on top of the second region, or vice versa. If desired, the two
regions may be laminated to each other so as to provide a single
dosage form. In such embodiments, the first region may be dried
prior to laminating any additional regions thereto. Similarly, the
second region may be dried prior to laminating the first region
thereto. Alternatively, either the first or second region may be at
least partially dried prior to laminating any additional regions
thereto.
[0099] In such multi-region embodiments, there is provided a first
region, which includes a first polymeric matrix and a
therapeutically effective amount of an agonist. The agonist may be
a partial agonist, and the agonist may be an opioid agonist. One
such opioid agonist includes buprenorphine, but any desired agonist
may be used to treat the particular symptom desired. The first
region desirably includes a first buffering system in an amount
sufficient to provide a local pH of the agonist so as to optimize
the release and/or absorption of the agonist. The first region may
be in communication with a second region. The second region may
include a second polymeric matrix and a therapeutically effective
amount of an antagonist. One such antagonist includes naloxone, but
any desired antagonist may be used as desired. The second region
may further include a second buffering system in an amount
sufficient to provide a local pH of the antagonist so as to inhibit
the absorption of the antagonist. In some embodiments, it may be
desirable to have one region be dissolved at a faster rate than the
second region when it is placed into the mouth of the user. For
example, it may be desired to have the region including an
antagonist dissolve at a faster rate than the region including an
agonist, or vice versa.
[0100] In such multi-region film dosages, the first and second
regions may work in cooperation to provide a desired absorption
profile of the agonist and the antagonist. For example, the first
buffering system may be present in an amount sufficient to provide
increased absorption of the agonist, while the second buffering
system is present in an amount sufficient to provide a decreased
absorption of the antagonist. In some embodiments, the first
buffering system may be present in an amount sufficient to provide
a local pH of the first region so as to provide an optimum
absorption of the agonist, i.e., of from either about 3 to about 4
or of from about 4 to about 9, and more specifically from about 6
to about 9. In some embodiments, the second buffering system may be
present in an amount sufficient to provide a local pH of the second
region of from about 2 to about 4, and more specifically about 2 to
about 3. For a multi-region film dosage including buprenorphine in
the first region and naloxone in the second region, the local pH of
the buprenorphine region is desirably either from about 3 to about
4 or from about 5.5 to about 6.5, and the local pH of the naloxone
region is about 2.0 to about 3.0.
[0101] Depending on the particular agonist and antagonist
incorporated in the dosage, the desired local pH level for each
region may be greater or lower so as to optimize absorption of the
agonist while inhibiting absorption of the antagonist. Generally,
the local pH of the agonist-containing region is desirably between
about 4 to about 9, and most desirably about 6 to about 9. The
local pH for the antagonist-containing region is most desirably
about 2 to about 4. Again, however, it will be understood that the
particular agonist incorporated into the dosage may be more
optimally absorbed at a higher or lower pH.
[0102] The first and second buffering systems may be the same or
they may be different. Additionally, the first polymeric matrix and
the second polymeric matrix may be the same or they may be
different. Any desired levels of agonist and antagonist may be
provided, and desirably the dosage composition includes about 2 mg
to about 16 mg of the agonist and about 0.5 mg to about 4 mg of the
antagonist per dosage unit. More desirably, the dosage composition
includes about 4 mg to about 12 mg of the agonist and about 1 mg to
about 3 mg of the antagonist per dosage unit.
[0103] The first and second regions may be formed together in any
desired means. In one embodiment, the second region may be coated,
sprayed, or placed onto at least one surface of the first region.
Alternatively, the first and second regions may be co-extruded. In
some embodiments, the first and second regions may be laminated to
each other by means of a suitable composition. Further, the first
region may be formed first, and then subsequently dipped into a
solution of a wet composition, which is then allowed to dry and
form the second region. As will be understood by one of ordinary
skill in the art, the first region may include the antagonist while
the second region includes the agonist. Further, both regions may
include a desired amount of agonist and antagonist so as to provide
a desired release and absorption.
[0104] The first region may include more components by weight than
the second region, or vice versa. For example, the first region may
have a total weight that is more than the total weight of the
second region, or vice versa. Alternatively, the first and second
regions may include the same amount of components by weight.
[0105] In another embodiment, there may be provided a
self-supporting film dosage composition having more than one
region, where each region includes a polymeric matrix and a
water-soluble and/or a water-insoluble active. The dosage
composition preferably includes a therapeutically effective amount
of a water-soluble active and a therapeutically effective amount of
water-insoluble active. Each region preferably includes a buffer in
an amount sufficient to control the absorption profiles of the
water-soluble and water-insoluble actives in each region, depending
on the desired level of absorption of the active desired. In one
desired embodiment, a first buffer is present in the first region
in an amount sufficient to obtain a local pH of one region of about
2 to about 4, while a second buffer is present in the second region
in an amount sufficient to obtain a local pH of the second region
of about 4 to about 9.
[0106] The present invention provides a method of treating various
problems in a patient, including, for example physical pain
experienced by a patient. Desirably, the patient is treated by
providing a dosage to the patient, which provides an effective
release of therapeutic active but simultaneously provides a
suitable adhesion so that the dosage cannot be easily removed. The
dosage forms provided herein are particularly useful in preventing
diversion of a drug. In one method of treatment, an orally
dissolvable film composition is provided to a patient.
[0107] Depending on the particular symptom sought to be treated,
the film composition may include one or more particular active
components. In one embodiment, the film composition includes a
polymer carrier matrix and a therapeutically effective amount of an
agonist. Desirably the agonist is a partial agonist. For some types
of pain, the agonist may be an opioid agonist, such as
buprenorphine or a pharmaceutically acceptable salt thereof. The
film composition preferably includes a buffer in an amount
sufficient to control the local pH of the film composition. Any
buffer or buffering system may be used, including those listed
above. Desirably, the local pH of the film composition including an
agonist is buffered to be about 4 to about 9, depending on the
particular agonist included in the composition. In some
embodiments, such as when the agonist is buprenorphine, the desired
local pH is about 5 to about 6.5, and most desirably the local pH
is about 5.5 to about 6.5. At this level, the absorption of the
agonist may be optimized. To treat the pain, the film composition
is administered to the patient, most desirably into the oral cavity
of the patient, such as through buccal absorption.
[0108] If desired, the composition may include a therapeutically
effective amount of an antagonist. As explained above, the
combination of an agonist and antagonist may help minimize
potential abuse of the agonist. The antagonist may be any desired
antagonist, and in one embodiment includes naloxone or a
pharmaceutically acceptable salt thereof. The film composition is
preferably administered to patient through the oral cavity of the
patient, but may be administered in any desired means. The orally
dissolvable film composition is then allowed to dissolve in the
oral cavity of the patient for a sufficient time so as to release
the active(s) therein. In some embodiments, the film composition
may remain in the oral cavity for at least 30 seconds, and in some
embodiments may remain in the oral cavity for at least 1 minute.
After the film composition is placed into the oral cavity of the
patient, the film preferably becomes sufficiently adhered so as to
render its removal difficult. After the film composition has been
administered to the patient, the active(s) are sufficiently
released from the composition and allowed to take effect on the
patient.
[0109] In embodiments where there is a dual-region film
composition, the administration of the dosage may have regions of
differing dissolution rates. For example, the first region of the
film composition may include an agonist and a moderate dissolving
polymer. Desirably, the first region remains in the oral cavity for
at least one minute, and up to about 30 minutes. The second region,
which may include an antagonist, desirably contains a fast
dissolving polymer. As such, the second region dissolves within
less than one minute, thereby releasing the antagonist into the
body where it is ingested and ionized. In this way, the antagonist
is swallowed, thereby avoiding buccal absorption. However, the
antagonist is still present in the film composition before
administration so as to limit potential abuse of the drug should a
user attempt to extract the agonist from the composition.
[0110] The film compositions of the present invention may be formed
via any desired process. Suitable processes are set forth in U.S.
Pat. Nos. 7,425,292 and 7,357,891, the entire contents of which are
incorporated by reference herein. In one embodiment, the film
dosage composition is formed by first preparing a wet composition,
the wet composition including a polymeric carrier matrix, a
therapeutically effective amount of an agonist, and a buffer in an
amount sufficient to control the local pH of the composition to a
desired level. The wet composition is cast into a film and then
sufficiently dried to form a self-supporting film composition. The
wet composition may be cast into individual dosages, or it may be
cast into a sheet, where the sheet is then cut into individual
dosages. The agonist may be a partial agonist. If desired, the wet
composition may include a therapeutically effective amount of an
antagonist. In some embodiments, especially in single-region
dosages, the local pH of the film may be about 2 to about 4, and
more particularly between about 3 to about 4.
[0111] The agonist and the optional antagonist are preferably
selected to treat a particular problem, such as treatment of
physical pain suffered by a patient. For example, the agonist may
include buprenorphine or a pharmaceutically acceptable salt
thereof, while the antagonist may include naloxone or a
pharmaceutically acceptable salt thereof. The film composition
includes at least one buffer or buffering system so as to control
the local pH of the agonist and antagonist to desired levels. In
this fashion, the absorption of the agonist may be optimized while
the absorption of the antagonist may be inhibited. In one desired
embodiment, the inventive film provides an absorption of the
agonist that is bioequivalent to that of a Suboxone.RTM.
tablet.
[0112] If the desired optimum absorption of the agonist is to
provide a bioequivalent absorption to that of a Suboxone.RTM.
tablet, the local pH of the film composition should provide a local
pH of the agonist of either between about 3 to about 4 or between
about 5.5 to about 6.5, and a local pH of the antagonist of between
about 2 to about 4. In a film composition including only one region
with the agonist and antagonist, the local pH is desirably about 3
to about 4 to provide a bioequivalent absorption to the
Suboxone.RTM. tablet.
[0113] Active ingredients in pharmaceutical compositions can
degrade and lose their effectiveness when included in a
pharmaceutical composition and stored. In certain cases, the active
ingredient may oxidize into a form that is, for example, less
bioavailable.
[0114] To minimize or prevent oxidation of the active, the film may
be manufacture in whole or in part under an inert gas environment.
A preferred inert gas is nitrogen.
[0115] Applicants have surprisingly discovered that chelators may
be employed to reduce or eliminate the oxidation of active
ingredients in film compositions. In fact, chelators are more
effective than anti-oxidants in preventing or reducing oxidation of
some actives, such as naloxone.
[0116] In practice, a chelator is added to the compositions of the
present invention in the same manner as any other additive. In
certain embodiments, a chelator is added to one or more regions of
a multi-region film. In another embodiment, a chelator is added to
one or both regions of a dual region film. In these embodiments,
the chelator may be the same in each region or may differ between
regions.
EXAMPLES
Example 1
Composition of Buprenorphine/Naloxone Films at Various
Strengths
[0117] Film strips including a combination of buprenorphine and
naloxone were prepared. Four different strength film compositions
were prepared, which include a ratio of buprenorphine to naloxone
of 16/4, 12/3, 8/2, and 2/0.5. The compositions are summarized in
Table 1 below.
TABLE-US-00001 TABLE 1 Various Compositions of Film Dosages
Buprenorphine/Naloxone Films Components Unit Formula (mg per film
strip) Buprenorphine/Naloxone Ratios 16/4 12/3 8/2 2/0.5 Active
Components Buprenorphine HCl 17.28 12.96 8.64 2.16 Naloxone HCl
Dihydrate 4.88 3.66 2.44 0.61 Inactive Components Polyethylene
Oxide, NF 27.09 20.32 13.55 -- (MW 200,000) Polyethylene Oxide, NF
12.04 9.03 6.02 19.06 (MW 100,000) Polyethylene Oxide, NF 4.82 3.62
2.41 2.05 (MW 900,000) Sugar Alcohol 12.04 9.03 6.02 5.87 Flavor
6.0 4.5 3.0 2.4 Citric Acid, USP 5.92 4.44 2.96 2.96 HPMC 4.22 3.16
2.11 2.34 Sweetener 3.0 2.25 1.5 1.2 Sodium Citrate, anhydrous 2.68
2.01 1.34 1.34 Colorant 0.03 0.02 0.01 0.01 Total (mg) 100 75 50
40
Example 2
Absorption Studies for Suboxone.RTM. Tablets
[0118] Various film and tablet products were prepared and tested
for absorption data, including Cmax and AUC absorption levels. The
products tested included Suboxone.RTM. tablets made with either 2
mg or 16 mg buprenorphine as well as either 0.5 mg or 4.0 mg
naloxone. For 16 mg buprenorphine tablets, two 8 mg buprenorphine
tablets were combined together to provide the level of components
of a 16 mg buprenorphine tablet. In instances where a 12 mg
buprenorphine tablet was evaluated, this dosage was obtained by
combining one 8 mg buprenorphine tablet and two 2 mg buprenorphine
tablets. These products were tested for absorption levels, with the
amounts listed in Table 2 below.
TABLE-US-00002 TABLE 2 Absorption Data for Suboxone .RTM. products
Sample C max AUC Buprenorphine (2 mg) 0.780 ng/ml 6.789 hr*ng/ml
Suboxone .RTM. Tablet Naloxone (0.5 mg) 51.30 pg/ml 128.60 hr*pg/ml
Suboxone .RTM. Tablet Buprenorphine (16 mg) 4.51 ng/ml 44.99
hr*ng/ml Suboxone .RTM. Tablet Naloxone (4 mg) 259.00 pg/ml 649.60
hr*pg/ml Suboxone .RTM. Tablet
[0119] Using the data from Table 2, absorption data for the
Suboxone.RTM. tablets for other levels of buprenorphine and
naloxone are set forth in Table 2A below.
TABLE-US-00003 TABLE 2A Absorption Data for Suboxone .RTM. tablets
Sample C max AUC Buprenorphine (4 mg) 1.35 ng/ml 12.25 hr*ng/ml
Suboxone .RTM. Tablet Naloxone (1 mg) 80.97 pg/ml 203 hr*pg/ml
Suboxone .RTM. Tablet Buprenorphine (8 mg) 2.29 ng/ml 23.17
hr*ng/ml Suboxone .RTM. Tablet Naloxone (2 mg) 140.31 pg/ml 351.8
hr*pg/ml Suboxone .RTM. Tablet Buprenorphine (12 mg) 3.23 ng/ml
34.08 hr*ng/ml Suboxone .RTM. Tablet Naloxone (3 mg) 199.7 pg/ml
500.6 hr*pg/ml Suboxone .RTM. Tablet
Example 3
Evaluation of Bioequivalence of Suboxone.RTM. Tablets
[0120] Using the data generated for Suboxone.RTM. tablets in Table
2 above, acceptable bioequivalence ranges are generated so as to
provide an equivalent treatment level as the Suboxone.RTM. tablet.
As currently understood, a product provides a bioequivalent effect
if it provides absorption levels between about 80% to about 125% of
the Suboxone.RTM. tablet. Absorption in this range is considered to
be bioequivalent.
TABLE-US-00004 TABLE 3 Acceptable Bioequivalence Ranges for
Suboxone .RTM. Tablets (80 to 125%) Description of Sample C max AUC
Buprenorphine 0.624 to 0.975 ng/ml 5.431 to 8.486 hr*ng/ml 2 mg
Naloxone 41.04 to 64.13 pg/ml 102.88 to 160.75 hr*pg/ml 0.5 mg
Buprenorphine 3.608 to 5.638 ng/ml 35.992 to 56.238 hr*ng/ml 16 mg
Naloxone 207.20 to 323.75 pg/ml 519.68 to 812.00 hr*pg/ml 4 mg
[0121] Thus, to be considered bioequivalent to the Suboxone.RTM.
tablet, the Cmax of buprenorphine is between about 0.624 and 5.638,
and the AUC of buprenorphine is between about 5.431 to about
56.238. Similarly, to be considered bioequivalent to the
Suboxone.RTM. tablet, the Cmax of naloxone is between about 41.04
to about 323.75, and the AUC of naloxone is between about 102.88 to
about 812.00.
Example 4
Composition of Buprenorphine Films at Various Strengths
[0122] Film strips including a buprenorphine were prepared. Two
different strength film compositions were prepared, which include
buprenorphine in a dosage amount of 8 mg and in a dosage amount of
2 mg. The compositions are summarized in Table 4 below.
TABLE-US-00005 TABLE 4 Various Compositions of Film Dosages
Buprenorphine Films Components Unit Formula (mg per film strip)
Buprenorphine 8.64 2.16 Inactive Components Polyethylene Oxide, NF
17.66 21.87 (MW 100,000) Polyethylene Oxide, NF 2.17 2.35 (MW
900,000) Sugar Alcohol 5.43 6.72 Flavor 2.8 2.8 HPMC 1.9 2.69
Sweetener 1.2 1.2 Colorant 0.2 0.2 Total (mg) 40 40
Example 5
Cmax and AUCinf Levels for Film Strips Incorporating
Buprenorphine
[0123] Five film dosage compositions were prepared, each including
buprenorphine in a dosage of from 2 mg to 16 mg. Table 5 below sets
forth Cmax and AUCinf levels for various dosage levels of film
compositions including buprenorphine.
TABLE-US-00006 TABLE 5 Cmax and AUCinf Levels for Film Strips
Incorporating Buprenorphine Buprenorphine Cmax AUCinf 2 mg 0.7-1.07
ng/ml 6.8-9.5 hr ng/ml 4 mg 1.2-1.84 ng/ml 11.2-16.7 hr ng/ml 8 mg
2.3-3.8 ng/ml 22.7-34.1 hr ng/ml 12 mg 2.8-5.2 ng/ml 30.4-48.6 hr
ng/ml 16 mg 4.08-6.4 ng/ml 42.6-65.8 hr ng/ml
Example 6
Preparation of Films for In Vivo Study
[0124] Film dosages were prepared for use in an in vivo study to
determine the bioavailability of buprenorphine/naloxone tablets and
film formulations. Specifically, the films were tested to determine
whether the film provides a bioequivalent effect to that of a
tablet formulation.
[0125] Three film formulations including 8 mg buprenorphine and 2
mg naloxone were prepared, each being buffered to a different pH.
The first film did not include any buffer, providing a local pH of
about 6.5. The second was buffered to a local pH level of about
3-3.5. The third was buffered to a local pH value of about 5-5.5.
The formulations are set forth in Table 6 below.
TABLE-US-00007 TABLE 6 Formulations of Test Films at Various pH
Levels Test Test Test formulation 1 formulation 2 formulation 3 8
mg/2 mg 8 mg/2 mg 8 mg/2 mg pH = 6.5 pH = 3-3.5 pH = 5-5.5 % Mg/ %
Mg/ % Mg/ Component w/w film w/w film w/w film Buprenorphine 21.61
8.64 17.28 8.64 17.28 8.64 HCl Naloxone HCl 6.10 2.44 4.88 2.44
4.88 2.44 Dihydrate Polymer 5.05 2.02 4.82 2.41 4.82 2.41 Polymer
28.48 11.39 27.09 13.55 27.09 13.55 Polymer 12.65 5.06 12.04 6.02
12.04 6.02 Polymer 4.43 1.77 4.22 2.11 4.22 2.11 Sweetener 12.65
5.06 12.04 6.02 12.04 6.02 Sweetener 3 1.2 3 1.5 3 1.5 Flavor 6 2.4
6 3 6 3 Citric acid 0 0 5.92 2.96 2.51 1.26 Sodium citrate 0 0 2.68
1.34 6.08 3.04 FD&C yellow 0.025 0.01 0.03 0.02 0.03 0.02 #6
Total 100 40 100 50 100 50
Example 7
Analysis of In Vivo Absorption of Film Having a pH of 6.5
[0126] The film dosage composition of film having a local pH of 6.5
was analyzed. Specifically, Test Formulation 1, as prepared in
Example 5 was analyzed in vivo to determine the absorption of
buprenorphine and of naloxone. The comparative film was compared to
the absorption of buprenorphine and of naloxone provided by a one
dose tablet (Suboxone.RTM.). The test film was compared to
determine whether it provided a bioequivalent effect as the
Suboxone.RTM. tablet.
[0127] The results for Test Formulation 1, which had a local pH of
about 6.5, as compared to the one dose tablet, are set forth in
Tables 7 and 8 below.
TABLE-US-00008 TABLE 7 Buprenorphine In Vivo Absorption Data for
Test Formulation 1 Suboxone .RTM. Test Formulation 1 sublingual (pH
= 6.5) CV CV Parameter n Mean SD % n Mean SD % T.sub.max (hr) 15
1.60 0.47 29.41 15 1.50 0.62 41.23 C.sub.max 15 2.27 0.562 24.77 15
2.60 0.872 33.53 (ng/mL) AUC.sub.last 15 27.08 10.40 38.41 15 31.00
12.93 41.72 (hr*ng/ mL) AUC.sub.inf 15 29.58 11.15 37.68 15 33.37
13.88 41.61 (hr*ng/ mL) T.sub.1/2 (hr) 15 44.76 20.86 46.60 15
40.73 14.93 36.66
TABLE-US-00009 TABLE 8 Naloxone In Vivo Absorption Data for Test
Formulation 1 Suboxone .RTM. Test Formulation 1 sublingual (pH =
6.5) CV CV Parameter n Mean SD % n Mean SD % T.sub.max (hr) 15 0.90
0.23 25.32 15 0.68 0.18 25.75 C.sub.max 15 94.6 39.1 41.33 15 410
122 29.75 (pg/mL) AUC.sub.last 15 297.1 120.7 40.62 15 914.8 158.1
17.29 (hr*pg/ mL) AUC.sub.inf 15 306.1 122.6 40.06 15 924.2 158.8
17.18 (hr*pg/ mL) T.sub.1/2 (hr) 15 6.62 2.60 39.26 15 6.86 2.08
30.27
[0128] As can be seen, the in vivo data indicates that
buprenorphine is absorbed very well from the film formulation at a
local pH of 6.5, and matched closely the absorption seen in the
Suboxone.RTM. one dose tablet. However, the absorption was also
maximized for the naloxone, which was undesirable. It was
determined that a film having a combination of buprenorphine and
naloxone and a local pH of 6.5 did not provide a bioequivalent
effect as the one dose Suboxone.RTM. tablet for both buprenorphine
and naloxone.
Example 8
Analysis of In Vivo Absorption of Film Having a pH of 5-5.5
[0129] Having determined the absorption of buprenorphine and
naloxone in film having a local pH of 6.5, a film dosage
composition of film having a local pH of 5-5.5 was analyzed.
Specifically, Test Formulation 3, as prepared in Example 5 was
analyzed in vivo to determine the absorption of buprenorphine and
of naloxone. The comparative films were compared to the absorption
of buprenorphine and of naloxone provided by a one dose tablet
(Suboxone.RTM.). The test film was compared to determine whether it
provided a bioequivalent effect as the tablet product.
[0130] The results for Test Formulation 3, which had a local pH of
about 5-5.5, as compared to the one dose tablet, are set forth in
Tables 9 and 10 below.
TABLE-US-00010 TABLE 9 Buprenorphine In Vivo Absorption Data for
Test Formulation 3 Suboxone .RTM. Test Formulation 3 sublingual (pH
= 5-5.5) CV CV Parameter n Mean SD % n Mean SD % T.sub.max (hr) 15
1.60 0.47 29.41 14 1.50 0.43 28.50 C.sub.max 15 2.27 0.562 24.77 14
3.47 1.57 45.40 (ng/mL) AUC.sub.last 15 27.08 10.40 38.41 14 33.25
16.01 48.16 (hr*ng/ mL) AUC.sub.inf 15 29.58 11.15 37.68 13 38.34
15.38 40.13 (hr*ng/ mL) T.sub.1/2 (hr) 15 44.76 20.86 46.60 13
41.71 17.70 42.42
TABLE-US-00011 TABLE 10 Naloxone In Vivo Absorption Data for Test
Formulation 3 Suboxone .RTM. Test Formulation 3 sublingual (pH =
5-5.5) CV CV Parameter n Mean SD % n Mean SD % T.sub.max (hr) 15
0.90 0.23 25.32 14 0.98 0.62 63.51 C.sub.max 15 94.6 39.1 41.33 14
173 84.5 48.79 (pg/mL) AUC.sub.last 15 297.1 120.7 40.62 14 455.2
195.5 42.94 (hr*pg/ mL) AUC.sub.inf 15 306.1 122.6 40.06 13 474.4
203.1 42.81 (hr*pg/ mL) T.sub.1/2 (hr) 15 6.62 2.60 39.26 13 9.45
6.90 73.00
[0131] As can be seen, the in vivo data indicated that the
absorption of buprenorphine increased as the local pH level
decreased. It appeared that by decreasing the local pH from 6.5 to
5.5, the absorption of buprenorphine was being moved to a level
much greater than that of the one dose Suboxone.RTM. tablet. In
addition, the naloxone values did not provide a bioequivalent
result as the one dose tablet. Thus, it was determined that the
film having a local pH of 5.5 did not provide a bioequivalent
result as that of the Suboxone.RTM. tablet for both buprenorphine
and naloxone.
[0132] It was noted that by reducing the local pH of the film to a
level of 5.5, there would be provided an increased level of
absorption of buprenorphine. Thus, it may be desirable to buffer a
film composition incorporating buprenorphine itself to a level of
about 5.5 to provide an increased absorption.
Example 9
Analysis of In Vivo Absorption of Film Having a pH of 3-3.5
[0133] Having determined the absorption of buprenorphine and
naloxone in films having a local pH of 6.5 and 5.5, a film dosage
composition of film having a local pH of about 3-3.5 was analyzed.
It was assumed that the absorption of buprenorphine would continue
to be increased as it had demonstrated at a local pH of 5.5. Thus,
it was assumed that at a local pH of 3.5, the film would not be
bioequivalent to that of the tablet.
[0134] Specifically, Test Formulation 2, as prepared in Example 5,
was analyzed in vivo to determine the absorption of buprenorphine
and of naloxone. The comparative films were compared to the
absorption of buprenorphine and of naloxone provided by a one dose
tablet (Suboxone.RTM.). The test film was compared to determine
whether it provided a bioequivalent effect as the tablet
product.
[0135] The results for Test Formulation 2, which had a local pH of
about 3-3.5, as compared to the one dose tablet, are set forth in
Tables 11 and 12 below.
TABLE-US-00012 TABLE 11 Buprenorphine In Vivo Absorption Data for
Test Formulation 2 Suboxone .RTM. Test Formulation 2 sublingual (pH
= 3-3.5) CV CV Parameter n Mean SD % n Mean SD % T.sub.max (hr) 15
1.60 0.47 29.41 14 1.68 0.58 34.68 C.sub.max 15 2.27 0.562 24.77 14
2.68 0.910 33.99 (ng/mL) AUC.sub.last 15 27.08 10.40 38.41 14 29.73
12.05 40.54 (hr*ng/ mL) AUC.sub.inf 15 29.58 11.15 37.68 14 31.45
12.98 41.26 (hr*ng/ mL) T.sub.1/2 (hr) 15 44.76 20.86 46.60 14
30.03 13.95 46.46
TABLE-US-00013 TABLE 12 Naloxone In Vivo Absorption Data for Test
Formulation 2 Suboxone .RTM. Test Formulation 2 sublingual (pH =
3-3.5) CV CV Parameter n Mean SD % n Mean SD % T.sub.max (hr) 15
0.90 0.23 25.32 14 0.84 0.19 22.19 C.sub.max 15 94.6 39.1 41.33 14
130 72.9 56.04 (pg/mL) AUC.sub.last 15 297.1 120.7 40.62 14 362.2
155.9 43.03 (hr*pg/ mL) AUC.sub.inf 15 306.1 122.6 40.06 12 350.4
142.3 40.61 (hr*pg/ mL) T.sub.1/2 (hr) 15 6.62 2.60 39.26 12 8.07
4.75 58.84
[0136] As can be seen, the in vivo data indicated that the
absorption of buprenorphine was substantially bioequivalent to that
of the one dose tablet when the film composition local pH was
lowered to about 3-3.5. This result was surprising as it did not
appear to follow the pH partition theory. Further, at a local pH of
about 3-3.5, it was seen that the absorption of naloxone was
substantially bioequivalent to that of the one dose tablet.
[0137] Thus, it was determined that the film product including
buprenorphine and naloxone at a local pH of 3-3.5 was substantially
bioequivalent to that of the Suboxone.RTM. one dose tablet. It was
therefore evident that one could formulate the naloxone at a local
pH of 3.5 or lower to inhibit its absorption, and formulate the
buprenorphine at a local pH of about 5.5 to optimize its
absorption.
Example 10
Normalized Values for Naloxone in Films and Tablets
[0138] Various film compositions including buprenorphine and
naloxone in 8/2 mg and 2/0.5 mg dosages, and having different local
pH values from 6.5 to 3.5, were prepared and analyzed. The data was
normalized and compared to the one dose Suboxone.RTM. tablet. The
results are set forth in Table 13 below.
TABLE-US-00014 TABLE 13 Normalized Values for Naloxone Film
Compared to Tablet Dose (g) Mg Ratio Citric Buprenorphine/ AUC
Citric Acid (mg)/ pH Naloxone (Normalized) Cmax Acid Naloxone (mg)
6.5 8/2 3.02 4.33 1.34 0.67 5.5 8/2 1.55 1.83 1.34 0.67 3.5 8/2
1.14 1.37 1.34 0.67 3.5 .sup. 2/0.5 0.98 0.90 1.34 2.68 5.5 .sup.
2/0.5 1.41 1.41 1.34 2.68
[0139] The data indicates that not only is the local pH of
significant importance, but the amount of acid present in the
formula is also important. The improvement from the 8/2 dose to the
2/0.5 dose (at a local pH of 3.5) demonstrates this importance. The
8/2 dose has a ratio of acid/naloxone of 0.67, and this dose
provided borderline acceptable bioequivalent results. In contrast,
the 2/0.5 dose has a ratio of acid/naloxone of 2.68 at a local pH
of 3.5, and provides a more bioequivalent absorption value than the
8/2 dose.
[0140] In fact, the data shows that the 2/0.5 dose at a local pH of
3.5 had an even lower buccal absorption than the one dose tablet,
as seen from the normalized values for the AUC and Cmax. This
demonstrates that even less absorption of the naloxone occurs for
the film formulation at a local pH of 3.5 than the tablet
formulation. Given the goal of reducing the absorption of naloxone,
it appears that the film product buffered at a local pH of 3.5 with
a buffer ratio (buffer/naloxone) of 2.68 provides even better
results than the Suboxone.RTM. formulation.
Example 11
Absorption Data for Dual-Film Dosage at Local pH 3.5 and Local pH
5.5
[0141] A dual-film dosage is prepared, with the first film layer
having a local pH of about 3.5 and containing an antagonist
therein, and the second film layer having a local pH of about 5.5
and containing an agonist therein. In this dual-film dosage, the
first film layer (having the antagonist) is a fast-dissolving film,
while the second film layer (having the agonist) is a moderate
dissolving film. Using data from the above studies, absorption
levels for various amounts of product in the film is presented in
Table 14 below:
TABLE-US-00015 TABLE 14 Extrapolated Absorption Data for
Dual-Layered Film at Agonist Local pH of 3.5 and Naloxone Local pH
of 5.5 Dose (mg agonist/ Naloxone Naloxone AUC mg naloxone) Cmax
(pg/ml) (hr*pg/ml) .sup. 2/0.5 32.5 90.5 8/2 130 362 16/4 260
724
[0142] Therefore, at amounts of 0.5-4.0 mg, the Cmax level for the
Naloxone is between about 32.5 to about 260 pg/ml and the AUC for
the Naloxone is between about 90.5 to about 724 hr*pg/ml. As will
be understood, varying types and levels of buffers may increase or
decrease the absorption values. That is, when seeking to inhibit
the absorption of the antagonist (i.e., naloxone), one may select a
particular local pH for the agonist region and a second local pH
for the antagonist region. The local pH of the region may depend on
the amount of active included in that region. The amounts of
actives incorporated into the dosage may be altered to provide
suitable absorption levels, and may include amounts in milligrams,
nanograms, picograms, or any desired amount of active.
Example 12
Comparison of Antioxidants and Stabilizing Agents on the Stability
of Naloxone in a 8/2 mg (Buprenorphine/Naloxone) Film
Formulation
[0143] Lab scale batches of 8/2 mg (Buprenorphine/Naloxone) film
dosage units containing the following excipients were produced as
previously described: [0144] 1. Ascorbic Acid [0145] 2. EDTA
(Ethylenediaminetetraacetic Acid Disodium Salt) [0146] 3. BHT
(Butylated Hydroxytoluene) [0147] 4. Propyl Gallate [0148] 5.
Sodium sulfite [0149] 6. Citric Acid [0150] 7. Sodium Metabisulfite
[0151] 8. Stabilizer System containing Ascorbic Acid, EDTA, Sodium
metabisulfite, BHT.
[0152] Samples were stored for 4 weeks at 60.degree. C. and a
relative humidity of 57%. The amounts of naloxone and oxidation
products of naloxone, 5-hydroxy naloxone (5HN), naloxone n-oxide
(NNO), and noroxymorphone (NOMP) were then determined. The results
are reported in Table 15:
TABLE-US-00016 TABLE 15 4 Week Stability Naloxone/Antioxidant Study
% Naloxone % 5HN % NNO % NOMP Sample No. Initial 4 Weeks Initial 4
Weeks Initial 4 Weeks Initial 4 Weeks Control 109.9 101.2 0.1723
0.910 0.0260 ND 0.1358 0.64 Ascorbic 1 104.7 94.3 0.0908 0.44 ND ND
0.1115 0.16 Acid EDTA 2 105.6 102.0 0.0385 0.18 0.0028 ND 0.1262
0.17 BHT 3 105.3 100.4 0.0906 0.86 ND ND 0.1365 0.30 Propyl 4 102.6
97.7 0.3057 0.90 ND ND 0.1565 0.25 Gallate Na 5 104.7 98.1 0.0991
1.14 0.0035 ND 0.1318 0.53 Sulfite Citric 6 105.1 98.1 0.1208 1.38
ND ND 0.1374 0.66 Acid Na Metabi- 7 64.2 55.8 0.0395 0.12 ND ND
0.3855 2.47 Sulfite Stabilizer 8 112.3 105.1 0.0466 0.01 ND ND
0.1482 0.91 System
[0153] The addition of the stabilizer system and EDTA had a
positive impact on the production of 5HN. The addition of sodium
sulfite, BHT, citric acid and propyl gallate had no improvement
over control.
[0154] The addition of EDTA results in a reduction of 5HN from
0.91% to 0.18% after 4 weeks storage at 60.degree. C. and 75%
relative humidity. Thus, EDTA appears to be effective in
stabilizing naloxone in the film compositions.
Example 13
EDTA Concentration Study
[0155] The appropriate EDTA level to protect naloxone from
oxidation when used in the formulation of the 8/2 mg
(buprenorphine/naloxone) film was studied. Samples of the 8/2 mg
(buprenorphine/naloxone) films were produced with following amounts
of EDTA: 4.0 mg, 2.0 mg, 1.0 mg, 0.2 mg, and no EDTA (control).
[0156] The samples were stored at 60.degree. C. and 75% relative
humidity for 4 weeks and the combined content of 2 primary
oxidation product, 5HN and NNO was determined initially, at 2
weeks, and at 4 weeks for each formula. The results are reported in
FIG. 1.
[0157] Based on the incremental differences observed in the summed
levels of 5HN and NNO between the 2 mg EDTA sample and the 1 mg
EDTA sample, a 1 mg level of EDTA is sufficient to significantly
reduce oxidation of naloxone in the film product.
* * * * *