Note: Descriptions are shown in the official language in which they were submitted.
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1
PHARMACEUTICAL COMPOSITIONS
FOR RECTAL AND VAGINAL ADMINISTRATION
FIELD OF THE INVENTION
The present application relates to pharmaceutical compositions and methods of
delivering active ingredients through the rectum or vagina, and in particular
to compositions
and methods using effervescent agents as penetration enhancers to promote
rectal or vaginal
delivery of an active ingredient.
BACKGROUND OF THE INVENTION
Although generally not well accepted, various proposals have been advanced for
rectal and vaginal administration of drugs. Because some veins in the rectum
and vagina lead
directly to the general circulation, when drugs are administered through the
rectum or vagina,
they have the advantage of bypassing the gastrointestinal and heptic
metabolism process (i.e.,
reducing the first-pass effect). This can lead to faster onset of action
and/or improved
bioavailability of a drug. In addition, delivery of a drug through the rectum
and vagina can
be useful for patients unable or unwilling to take drugs orally or
intravenously.
To improve the bioavailability of poorly absorbed drugs across the rectal and
vaginal
mucosa, penetration enhancers have been employed. Penetration enhancers are
typically low
molecular weight compounds, which enhance drug absorption across the mucosal
membrane.
There are generally five major classes of penetration enhancers: (1) bile
salts and their
derivatives (e.g., taurcholate, deoxcholate, and glycocholate); (2) chelators
(e.g., citric acid,
enamines, EDTA); (3) fatty acids and their derivatives (e.g., arachidonic
acid, oleic acid,
sodium caprylate, monoolein); (4) surfactants (e.g, SDS, polyoxyethylene-20-
cetylether); and
nonsurfactants (e.g., 1-alkylazacycloalkanone unsaturated ureas). Penetration
eiihancers are
thought to increase drug permeability by affecting the membrane transport
pathways and/or
reducing the barrier effect of the mucosal lining.
Although generally effective, many of the penetration enhancers referred to in
the
current literature damage the absorbing tissues, often causing extensive
tissue damage.
Moreover, some penetration enhancers are also known to be toxic, such as bile
salts, and
therefore their use has been very limited. Accordingly, due to their side
effects, penetration
enhancers are often not a practical solution to the problem of poor
bioavailability in the
administration of active ingredients through rectum, vagina and elsewhere.
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Therefore, there is a need for safe and effective penetration enhancers for
the delivery
of active ingredients across the rectal and vaginal mucosa.
SUMMARY OF THE INVENTION
The pharmaceutical compositions of the present invention comprise rectal or
vaginal
dosage forms containing an active ingredient in combination with an
effervescent penetration
enhancer for improving absorption of the active ingredient across the rectal
and vaginal
mucosa membranes, respectively. The effervescent agent can be used alone or in
combination
with a pH adjusting substance that alters the pH of the localized environment
of the site of
dissolution and absorption in the rectum or vagina to further improve
dissolution and
absorption.
According to the present invention then, there is provided a dosage form
adapted for
rectal administration of a therapeutically effective amount of an active
ingredient to a target
area in the rectum of a mammal; comprising a therapeutically effective amount
of an active
ingredient; and at least one effervescent penetration enhancer; wherein said
at least one
effervescent penetration enhancer is present in an amount sufficient to
increase the penetration
of said active ingredient across said target area of said rectum, and to
permit delivery of a
therapeutically effective amount of said active ingredient.
According to a further aspect of the present invention, there is also provided
the use
of an effervescent penetration enhancer for delivering an active ingredient to
a target area in
the rectum of a mammal; comprising the steps of providing in the rectum of a
mammal a
dosage form comprising a therapeutically effective amount of an active
ingredient and at least
one effervescent penetration enhancer present in an amount sufficient to
increase absorption
of said active ingredient across a mucosa layer of said target area, causing
said active
ingredient and said effervescent penetration enhancer to release from said
dosage form at said
target area in said rectum and to provide effervescent action at said target
area; so that said
effervescent action promotes the absorption of a therapeutically effective
amount of said active
ingredient across said target area.
According to yet another aspect of the present invention, there is provided a
dosage
form adapted for vaginal administration of a therapeutically effective amount
of an active
ingredient to a target area in the vagina of a mammal; comprising a
therapeutically effective
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amount of an active ingredient; and at least one effervescent penetration
enhancer; wherein
said at least one effervescent penetration enhancer is present in an amount
sufficient to
increases the penetration of said active ingredient across said target area of
said vagina.
According to yet a further aspect of the present invention, there is also
provided the use
of an effervescent penetration enhancer for delivering an active ingredient to
a target area in
the vagina of a mammal; comprising the steps of providing in the vagina of a
mammal a
dosage form comprising a therapeutically effective amount of an active
ingredient and at least
one effervescent penetration enhancer present in an amount sufficient to
increase absorption
of said active ingredient across a mucosa layer of said target area, causing
said active
ingredient and said effervescent penetration enhancer to release from said
dosage form at said
target area in said vagina and to provide effervescent action at said target
area; so that said
effervescent action promotes the absorption of a therapeutically effective
amount of said active
ingredient across said target area.
According to the present invention then, there is provided a dosage form
adapted for
rectal administration of a therapeutically effective amount of an active
ingredient to a target
area in the rectum of a mammal, said target area comprising rectal mucosa;
comprising a
therapeutically effective amount of an active ingredient; and at least one
effervescent
penetration enhancer; wherein said at least one effervescent penetration
enhancer comprises
a pharmaceutically acceptable effervescent couple, said effervescent couple
comprising an acid
or equivalent thereof and a base or equivalent thereof and said base is
present in an amount
that is at least about twice the amount of said active ingredient (on a weight
basis) and said
effervescent couple is present in an amount sufficient to increase the
penetration of said active
ingredient across said rectal mucosa; and further comprising a pH adjusting
substance; wherein
said dosage form permits systemic delivery of a therapeutically effective
amount of said active
ingredient.
According to another aspect of the present invention then, there is also
provided a
method for delivering an active ingredient to a target area in the rectum of a
mammal, said
target area comprising rectal mucosa; comprising the steps of administering to
the rectum of
said mammal a dosage form comprising a therapeutically effective amount of an
active
ingredient; and at least one effervescent penetration enhancer comprising a
pharmaceutically
acceptable effervescent couple, said effervescent couple comprising an acid or
equivalent
thereof and a base or equivalent thereof and said base is present in an amount
that is at least
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about twice the amount of said active ingredient (on a weight basis) and said
effervescent
couple present in an amount sufficient to increase penetration of said active
ingredient across
said rectal mucosa; and a pH adjusting substance; causing said active
ingredient and said
effervescent penetration enhancer to release from said dosage form at said
target area in said
rectum and providing effervescent action at said target area thereby promoting
penetration of
a therapeutically effective amount of said active ingredient across said
target area for systemic
delivery to said mammal.
According to a further aspect of the present invention then, there is also
provided a
dosage form adapted for vaginal administration of a therapeutically effective
amount of an
active ingredient to a target area in the vagina of a mammal, said target area
comprising
vaginal mucosa; comprising a therapeutically effective amount of an active
ingredient; and at
least one effervescent penetration enhancer; wherein said at least one
effervescent penetration
enhancer comprises a pharmaceutically acceptable effervescent couple, said
effervescent
couple comprising an acid or equivalent thereof and a base or equivalent
thereof and said base
is present in an amount that is at least about twice the amount of said active
ingredient (on a
weight basis) and said effervescent couple is present in an amount sufficient
to increases the
penetration of said active ingredient across said vaginal mucosa; and further
comprising a Ph
adjusting substance; wherein said dosage form permits systemic delivery of a
therapeutically
effective amount of said active ingredient.
According to yet a further aspect of the present invention then, there is also
provided
a method for delivering an active ingredient to a target area in the vagina of
a mammal, said
target area comprising vaginal mucosa; comprising the steps of administering
in the vagina of
said mammal a dosage form comprising; a therapeutically effective amount of an
active
ingredient; and at least one effervescent penetration enhancer comprising a
pharmaceutically
acceptable effervescent couple, said effervescent couple comprising an acid or
equivalent
thereof and a base or equivalent thereof and said base is present in an amount
that is at lest
about twice the amount of said active ingredient (on a weight basis) and said
effervescent
couple present in an amount sufficient to increase penetration of said active
ingredient across
said vaginal mucosa; and a pH adjusting substance; causing said active
ingredient and said
effervescent penetration enhancer to release from said dosage form at said
target area in said
vagina and providing effervescent action at said target area thereby promoting
penetration of
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a therapeutically effective amount of said active ingredient across said
target area for systemic
delivery to said mammal.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The pharmaceutical compositions of the present invention comprise rectally and
vaginally administrable active ingredients in combination with an effervescent
agent for
influencing absorption of a drug in the rectum or vagina, respectively.
Effervescence leads to
an increase in the rate and/or the extent of absorption of the drugs, and in
particular, drugs that
are known or suspected of having poor bioavailability. It is believed that
such increase can
result from reducing the thickness and/or the viscosity of the mucus layer ;
alteration of the
tight junctions between cells, thus promoting absorption through the
paracellular route;
inducing a change in the cell membrane structure, thus promoting transcellular
absorption; and
increasing the hydrophobic environment within the cellular membrane.
The pharmaceutical compositions include an active ingredient, which is
administerable
through the rectum or vagina, depending on the selected route of
administration, and an
amount of effervescent agent effective to aid in penetration of the drug in
the rectum or vagina,
respectively. The amount of effervescent employed must not merely permit rapid
dispersion
of the medicament, but must aid in penetration of the drug across the rectal
or vaginal mucosa.
In this regard, the pharmaceutical compositions of the present invention may
be distinguished
from other effervescent compositions on the basis of the amount of
effervescent material that
they contain.
The term"effervescent penetration enhancer"includes compounds which evolve
gas.
The preferred effervescent penetration enhancers evolve gas by means of a
chemical reaction
which takes place upon exposure of the effervescent penetration enhancer to
small amounts
of water and other fluids in the recturn or vagina, respectively. Such water-
activated
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materials must be kept in a generally anhydrous state and with little or no
absorbed moisture
or in a stable hydrated form, since exposure to water will prematurely
disintegrate the
composition. The acid and base sources may be any which are safe for human or
mammalian
use. Suitable sources include acid and llydrite antacids such as, for example,
citric, tartaric,
amalic, fumeric, adipic, and succinics. Suitable base sources include
carbonate sources, such
as dry solid carbonate and bicarbonate salt, such as, preferably, sodium
bicarbonate, sodium
carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate
and the
like. The effervescent penetration enhancers of the present invention are not,
however,
limited to those that are based upon a reaction that forms carbon dioxide.
Reactants which
evolve oxygen or other gases and which are safe for human or maminalian use
are also
considered within the scope of the present invention.
The pharmaceutical compositions of the present invention should preferably
contain
at least about twice as much base as active ingredient (on a weight basis)
together with the
proportionate amount of an appropriate acid for generating the effervescent
reaction. More
preferably, the pharmaceutical compositions should contain at least about
three times as
much base as active ingredient (on a weight basis) together with the
proportionate amount of
an appropriate acid. It is particularly preferred that sufficient effervescent
material be
provided such that the evolved gas is more than 5 cm3, upon exposure of the
composition to
an aqueous environment in the rectum or vagina, respectively. These high
concentrations of
effervescent agents are needed to generate effervescence in sufficient amounts
to promote
permeability and absorption of the active ingredient across the rectal and
vaginal mucosa.
However, the amount of effervescent agent must be optimized for each specific
active
ingredient and for delivery in the rectum or vagina, respectively.
The pharmaceutical compositions may also include one or more pH adjusting
substances. For active ingredients that are weakly acidic or weakly basic, the
pH of the
aqueous environment can influence the relative concentrations of the ionized
and the
unionized forms of the active ingredient present in solution, according to the
Henderson-
Hasselbach equation. The pH of solutions in which an effervescent couple with
equimolar
amounts of base and acid has dissolved is slightly acidic due to the evolution
of COz. Thus,
the pH of the localized environment of the rectum or vagina (i.e., the
contents of the rectum
or vagina in immediate contact with the composition, including any active
ingredient
dissolved from the composition) may be altered to achieve desired relative
proportions of
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ionized and unionized active ingredients by incorporating in the compositions
certain pH
adjusting substances.
Suitable pH adjusting substances include any pH adjusting substance that is
safe for
mammalian use. More preferably, the pH adjusting substances include any weak
acid or weak
base. These include, but are not limited to, any of the acids or bases
previously mentioned as
the effervescent components, including, sodium carbonate, potassium carbonate,
disodium
hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium
salts.
The compositions may be administered in any dosage form suitable for delivery
of an
active ingredient to the rectum or vagina, respectively. For rectal
administration, these
compositions are preferably in the form of suppositories, tablets, capsules,
powders, granules,
microgranules, containing, in addition to the active ingredient and the
effervescent agent, such
carriers as are known in the art. For vaginal, administration, the
compositions are preferably
in the form of suppositories, vaginal rings, tablets, capsules, powders,
granules, microgranules,
containing, in addition to the active ingredient and the effervescent agent,
such carriers as are
known in the art. The suppositories and vaginal rings may be of a type that
dissolve completely
in the rectum or vagina, respectively, or remain intact following release of
the composition,
and subsequently removed. In general, the compositions may be prepared by
mixing the
ingredients using techniques well known to those skilled in the art for
producing these dosage
forms and for preparing effervescent pharmaceutical compositions, in which the
effervescent
materials must remain unreacted prior to administration of the composition.
In a preferred embodiment, the composition is administered in the form of a
tablet.
The tablets may, optionally, have special shapes to assist insertion of the
compressed dosage
form. These shapes include oval, capsule-shaped, and diamond-shaped tablets.
An applicator
device may also be supplied with the tablets to make insertion easier and to
facilitate insertion
deep into the rectal or vaginal cavity. Such applicators are commonly used in
the
pharmaceutical industry for this purpose.
The tablets may be matrix tablets, layered tables in which the various
components are
separated in different layers, or other specialized forms of tablets. The
tablets are preferably
manufactured by direct compression or any other tablet manufacturing technique
known in the
art. See, eg., U. S. Patents Nos. 5,178,878 and 5,223,264. Excipient fillers
can be used to
facilitate tableting. A filler desirably will also assist in the rapid
dissolution of the dosage
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form. Nonlimiting examples of suitable fillers include mannitol, dextrose,
lactose, and sucrose.
Pellets or other multiparticulates may be manufactured by granulation,
layering techniques,
extrusion and spheronization or other pellet manufacturing methods. Granules
may be made
by dry granulation process or any other granulation process known in the art.
Capsules can be
5 soft gelatin capsules, hard gelatin capsules and the like made according to
methods well
known in the art.
In another preferred embodiment, the composition is administered in the form
of a
suppository. These are solid, molded units that are formed by pouring into
suitable molds a
molten wax or fatty material or other suitable substance as the base, into
which is dissolved
or dispersed the active ingredient and the effervescent penetration agent, and
optionally, the
pH adjusting substance, noneffervescent penetration enhancers and other
excipients. Upon
cooling, the base forms a solid containing the active ingredient and other
ingredients dispersed
in it and takes the shape of the mold. Examples of bases that could be used
are cocoa butter,
polyethylene glycols, polyvinyl pyrrolidone, gelatin, gelatin/glycerin
combinations, esterfied
fatty acids, polyoxyethelene sorbitans and polyoxyethylene sorbitan fatty acid
esters. Various
additives may be incorporated including surfactants and absorption enhancers
such as medium
chain (C8 to C 12) fatty acids and fatty acid esters including mono-, di-, and
triesters of glycol.
Various bases, which may contain mixtures of different components, are also
available.
Examples of these are those sold under the trade names ImhausenTM, WitepsolTM
and
GelucireTM. Various grades of each of these are available for specific
applications. Mixtures
of various bases may also be utilized in order to obtain a suppository with
the required
properties. Other shaping methods for forming the suppositories including cold
molding and
compression may also be used.
In a more preferred embodiment, a suppository of the present invention may be
comprised of a suitable polyethylene glycol suppository base known in the art.
More
preferably, the polyethylene glycol suppository base is comprised of
polyethylene glycol and
polysorbate. A suitable commercially available polyethylene glycol suppository
base is
POLYBASE, manufactured by Paddock Laboratories, Inc. The polyethylene glycol
suppository base is present in the suppository-based delivery system in any
suitable amount
so as to allow the composition to be in contact with the rectal or vaginal
mucous membrane,
respectively. The polyethylene glycol suppository base confers a degree of
miscibleness with
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the mucous membrane surfaces of the rectum or vagina, wherein suspended
particles of the
compositions are in contact with such mucous membrane surfaces.
The suppository is preferably inserted into a laminate suppository shell which
forms
a molded shape. The suppository is stored in the shell until used. The
laminate suppository
shell is any shell known in the art suitable for packaging of the suppository.
The suppository
shell must be able to withstand temperatures of 60 C used in manufacturing
the
suppositories and temperatures of 4 C for long-term storage without
compromising the
integrity of the mold or reacting with the suppository in an unfavorable
manner. Preferably,
the laminate suppository shell is a polyvinyl chloride-polyethylene laminate
suppository shell.
A suitable commercially available laminate suppository shell is a polyvinyl
chloride-
polyethylene laminate suppository shell manufactured by Paddock Laboratories,
Inc.
The compositions may be formulated for rapid, immediate, delayed or sustained
release
or a combination of these release forms. For delayed or sustained release, for
example, the
active ingredient and the effervescent agent may be combined with one or more
coatings,
matrix materials or membranes, which prevent exposure of the active ingredient
and the
effervescent agent to the environment of the rectum or vagina, until a
predetermined time or
predetermined event. Suitable coating and matrix materials, include, for
example, materials
which are responsive to pH changes, materials which are metabolized by enzymes
present in
the rectum or vagina, respectively, and materials which dissolve after a
predetermined time
or exposure to a certain volume of liquid.
The active ingredients suitable for use in the present invention include any
active agent
suitable for delivery by either the rectum or the vagina, as desired.
Pharmaceutical ingredients
suitable for use in the present dosage forms may include, without limitation,
analgesics, anti-
inflammatories, antipyretics, antibiotics, antimicrobials, laxatives,
anorexics, antihistamines,
antiasthmatics, antidiuretics, antiflatuents, antimigraine agents,
antispasmodics, sedatives,
antihyperactives, antihypertensives, tranquilizers, decongestants, beta
blockers; peptides,
proteins, oligonucleotides and other substances ofbiological origin, and
combinations thereof.
Also encompassed by the term"active ingredient"are vitamins, minerals and
dietary
supplements as the same are defined, for example, in U. S. Patent No.
5,178,878.
More preferably, the active ingredients are drugs that display poor
bioavailability, slow
absorption or long tmaX. These active ingredients include small molecule
drugs,
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nutritional supplements (such as vitamins and minerals), proteins and peptides
and other
substances of biological origin. Examples of such drugs include, but are not
limited to, the
following:
Drug Bioavailability (%)
Acyclovir 15-30
Auranofin 15-25
Bretylium 23+9
Cyclosporine 23zL7
Cytarabine 20
Doxepin 27=L10
Doxorubicin 5
Hydralazine 16-35
Ketamine 20 7
Labetalol 1815
Mercaptopurine 12~:7
Methyldopa 25 16
Nalbuphine 25:L16
Naloxone 2
Pentoxifylline 19 13
Pyridostigmine 1 4:0
Terbutaline 14J:2
Verapamil 22 8
Riboflavin 11
Atenolol 50
Other ingredients or techniques may preferably be used with the present
compositions
to enhance the dissolution and absorption of the pharmaceutical ingredient
and/or to improve
the disintegration profile. These include, but are not limited to, the use of
additional chemical
penetration enhancers and materials that aid in release and/or penetration of
the drug in the
rectum or vagina, respectively. There are various mechanisms by which such
materials
promote release and penetration of the active ingredient, and this invention
is not limited to
any one mechanism.
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A bioadhesive polymer may preferably be included in the drug delivery device
to
increase the contact time between the dosage form and the rectal or vaginal
mucosa.
Nonlimiting examples of known bioadhesives used in the present invention
include: carbopol
(various grades), sodium carboxy methylcellulose, methylcellulose,
polycarbophil (NoveonTM
AA- 1), hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium
alginate, and sodium
hyaluronate.
Disintegration agents may also be employed to aid in dispersion of the drug in
the
rectum or vagina, respectively. Disintegration agents include, for example,
any
pharmaceutically acceptable effervescent agent. In addition to the
effervescence-producing
disintegration agents, a dosage form according to the present invention may
include suitable
noneffervescent disintegration agents. Nonlimiting examples of disintegration
agents include,
for example, microcrystalline cellulose, croscarmelose sodium, crospovidone,
starches and
modified starches.
Other excipients may be employed, such as fillers, agents used to insure
homogeneity
of the composition and agents used to aid in preparation, as are well-known in
the art.
Various modifications of the invention described herein will become apparent
to those
skilled in the art. Such modifications are intended to fall within the scope
of the appending
claims.
INDUSTRIAL APPLICABILITY
The invention relates to the pharmaceutical and medical industries and to the
production of dosage forms.
