Note: Descriptions are shown in the official language in which they were submitted.
1 3 1 3620 SA51
ORAL DRUG DELIVERY SYSTEMS
The present invention relates to an oral
drug delivery system which contains one or more
hydrophilic polymers, an ointment base, and
pullulan as a disintegrating agent, which system
when applied to an oral lesion, and upon absorption
of water, has high oral tissue affinity so that it
can retain active ingredients at the desired site
for p~rolonged periods without causing undue
irritation to the oral mucosa.
Drug delivery systems for delivering drugs
to the oral mucosa include tinctures, buccal
formulations and ointments. Tinctures are easily
applied to oral lesions but may be ingested into
the body within a relatively short time after
application. Buccal formulations may be retained
in the oral cavity for longer periods than
tinctures; however, they are usually larger in
size and thus uncomfortable to retain in the oral
cavity and often cause tissue irritation. In
addition, they may be separated from lesions by
1 3 1 3~20
-2- SA51
saliva or other exudate. Conventional ointment
formulations may be readily applied. However, in
many cases, they also may be readily removed from
the oral cavity by mechanical movement of the oral
tissue such as during speaking or eating. In
addition, conventional ointments may bleed during
storage or even after application. Moreover,
bleeding of active ingredients from ointments after
application to oral lesions may cause active
ingredients to be separated from such lesions and
carried by saliva to other locations in the oral
cavity.
A discussion of prior art patents relating
` to various drug delivery systems including oral
delivery systems and/or oral adhesives follows.
U. S. Patent No. 3,029,187 to Steinhardt
discloses anhydrous adhesive pharmaceutical
vehicles specifically designed for adhering
active ingredients to the oral mucosa which
vehicles are formed of an intimate mixture of
gelatin and a topically-acceptable vehicle such as
petrolatum, lanolin, benzoinated lard,
hydrogenated cotton seed oil, carboxymethyl
cellulose, pectin, karaya gum, tragacanth, Irish
moss extracts, alginates, polyvinyl pyrrolidone,
carbo gum, guar gum and pre-treated water-soluble
starch. Active ingredients which may be carried
by such vehicles include antiseptics, anesthetics,
steroids, hormones and antibiotics.
U. S. Patent No. 3,029,188 to Cyr et al
discloses gelatin oral adhesive pharmaceutical
preparations which include an intimate admixture
of particulate gelatin with mineral oil containing
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_3_ SA51
thickening agent, such as polyethylene, dispersed
therein. Cyr et al indicate that portions of the
gelatin may be substituted by other gums such as
carboxymethyl cellulose, pectin, karaya gum,
tragacanth, Irish moss extracts, alginates,
polyvinyl pyrrolidone, carob gum, guar gum and
pre-treated water-soluble starch.
U. s. Patent No. 3,312,594 ~o Cyr et al
discloses a long-lasting troche which contains a
lo medicament and equal portions of pectin, gelatin
and carboxymethylcellulose; the troche interacts
with saliva to dissolve in the mouth to form an
adhesive composition which secures and retains the
medicament to the oral mucosa.
U. S. Patent No. 3,984,571 to Chen discloses
a liquid carrier for a diagnostic or therapeutic
agent which liquid carrier includes a fine particle
size hydrocolloid, such as a cellulose ether,
suspended in a non-aqueous water-immiscible mobile
liquid. When a composition containing the
diagnostic or therapeutic agent in the liquid
carrier is made to contact a moist surface, the
mobile liquid is drained off and the hydrocolloid
(carrying the diagnostic or therapeutic agent)
attaches itself to the surface.
U. S. Patent No. 4,542,020 to Jackson et al
discloses antifungal suppository formulations
which are substantially free of water which
include an antifungal agent such as nystatin
together with a hydrocolloid, such as sodium
carboxymethyl cellulose or hydroxypropylmethyl
cellulose and a low melting suppository base.
1313h20
SA 5 1
--4--
Pullulan is a polysaccharide which is a
linear (poly) maltotriose llnked through ~ 6)
bonds on terminal glycopyranosyl groups of the
trisaccharide
S ~ ~Glc ~ ~Glc ~ ~Glc
and has a molecular weight ranging from 30,000 to
700,000. It thus has the structure
- ~- SA~l
~313620
r- ~
0
O ~ 0
L~X 0
1 5 O
0~
'~) V
20 5~ O~
~O~
a~,L~
o
3 5
1 3 1 362(~A51
Puliulan has been used in various pharma-
ceutical preparations including those disclosed in
the followina patents.
Japanese Patent 61109710 assigned to Taisho
Pharmaceut KK discloses suppositories for
treatment of hemorrhoids containing polyvinyl
alcohol (PVA), pectin, methyl or ethyl cellulose,
polyvinyl pyrrolidone, pullulan and/or tragacanth
rubber and an oleaginous base, such as cocoa
butter, lauric butter, hardened oil, fatty
glyceride or water soluble base such as
polyethylene glycol.
Japanese Patent No. 61112012 assigned to
Gelia Shinyaku Kogy discloses peroral slow-release
tablets containing (a) an active ingredient, (b) a
mono-, di- or tri-ester of sucrose such as sucrose
mono-, di- or tri-palmitate or stearate, and/or an
8-20 C higher fatty acid and (c) a water-soluble
high molecular weight substance such as
hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, polyvinyl pyrrolldone, methyl
cellulose, pullulan, dextrin, polyethylene glycol,
gum arabic, guar gum or mixtures.
Japanese Patent No. 60123417 assigned to
Nitto Electric Ind KK discloses a percutaneous
drug delivery device which contains a
pressure-sensitive adhesive layer which includes a
water-soluble high molecular weight substance
formed of a monomer having an ethylenically
unsaturated double bond and/or polysaccharides
such as polyvinyl alcohol, poly(meth)acrylic acid,
sodium poly(methy)acrylate, starch, pullulan,
agar-agar or dextrin.
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SA51
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U. S. Patent No. 4,540,602 to Motoyama
Shimesu et al discloses a process for preparing a
pharmaceutical composition containing a solid drug
in the form of finely divided particles no greater
than 10 microns in diameter, wherein a solid drug
which is substantially water-insoluble is
dissolved in a low-boiling hydrophobic organic
solvent, the resulting solution is emulsified in
water in the presence of a water-soluble high
molecular weight substance which is hydroxypropyl
cellulose, methyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methyl cellulose,
hydroxypropyl ethyl cellulose, carboxymethyl
cellulose sodium salt, alpha-starch, hydroxypropyl
starch, pullulan, gum arabic, tragacanth gum,
gelatin, polyvinyl alcohol, polyvinyl pyrrolidone
and mixtures thereof and water is thereafter
removed.
In accordance with the present invention, a
long-lasting bioadhesive oral ointment formulation
is provided which upon absorption of water has
improved retention of water-soluble or water-
insoluble medicament at a desired treatment site inthe oral cavity while causing less tissue irrita-
tion than prior art formulations. The bioadhesive
oral ointment formulation of the invention is formed
of a water-soluble or water-insoluble therapeuti-
cally active ingredient or medicament, a water-
soluble or water-insoluble hydrophilic polymer or
hydrocolloid which hydrates, becomes adhesive and
increases retention time of the medicament at the
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treatment site, pullulan as a disintegrating agent
and an ointment base composltion.
Thus, in essence, the ointment formula-
tion of the invent1on is easily applied and soon
after application at the desired site in accordance
with the aid of the pullulan releases a hydrophilic
polymer or hydrocolloid which adheres to the
membranes at the desired site and retains a uniform
distribution of medicament at the desired site to
lo provide long-lasting treatment.
The pullulan is essential in the ointment
formulation of the invention. It acts as a
disintegrating agent which controls the
disintegration of the ointment formulation to
release hydrophilic polymer and active
ingredient. The pullulan may be present in an
amount within the range of from about 2 to about
27% and preferably from about 16.7 to about 21.6%
by weight of the ointment formulation.
The ointment formulation of the invention
will also include a water-soluble or water-insoluble
medicament in an amount within the range of from
about 0.05 to about 25% by weight, and preferably
from about 0.05 to about 5% by weight, depending
upon the particular medicament employed, a hydro-
colloid to impart adhesive qualities, such as
gelatin and/or sodium carboxymethyl cellulose,
carrageenan or sodium alginate, in an amount within
the range of from about 5 to about 60% by weight
and preferably from about 15 to about 55% by weight,
and more preferably from about 18 to about 44% by
weight, and an ointment base in an amount within
the range of from about 25 to about 70% by weight
and preferably from about 30 to about 65% by
1 3 1 3620
SA51
weight, all of the above % being based on the total
weight of the ointment formulation.
The medicament which may be employed in the
ointment formulation of the invention may be
water-soluble or water-insoluble and may include
antifungal agents, such as amphotericin s, nystatin,
griseofulvin, miconazole, ketoconazole, tioconazole,
econazole, clotrimazole, and other macrolide
antifungal agents, antibacterials (such as metroni-
dazole, penicillins, ampicillin, neomycin,erythromycin, mupirocin, tyrothricln, gramicidin,
cephalosporins, gentamycin and other aminoglycosides,
anti-cancer agents (such as 5-fluorouracil),
anti~inflammatory agents (such as hydrocortisone,
other known steroids such as prednisone, predniso~
lone, triamcinolone, dexamethasone, and
betamethasone), hormones (such as oestriol),
analgesic and anti-inflammatory agents such as
acetaminophen, phenacetin, aspirin, aminopyrine,
sulpyrine, phenylbutazone, mefenamic acid,
flufenamic acid, Ibufenac, ibuprofen, indomethacin,
colchicine, and Probenecid, and anti-viral agents
(such as acyclovir, ribavarin, trifluorothyridine
or idoxuridine) antiseptics, hexachlorophene,
tetramethyl thiuramdisulfide, benzalkonium
chloride, thimerosal, hexylresorcinol, cresols,
zinc oxide, methylene blue, boric acid,
chloramine-T, gentian violet, phenyl mercuric
chloride, phenyl mercuric nitrate basic,
acriflavin, sodium perborate, metallic peroxides
(e.g. sodium peroxide), sodium permanganate, and
the halogens. The medicament will be present in an
amount within the range of from about 0.1 to about
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SA51
--10--
25% and preferably from about 0.2 to about 15% by
weight depending upon the particular medicament
employed and the desired site of action.
Ointment formulations containing such
medicaments in accordance with the present
invention may be administered up to two times per
day or any convenient regimen
The hydrophilic polymers or hydrocolloids
which may be present in the ointment formulation
of the invention are water-swellable polymeric
substances such as cellulosic polymers and gums.
The hydrocolloid will preferably comprise gelatin,
cellulose polymers which are cellulose ethers such
as methyl cellulose, cellulose alkyl hydroxylates
such as hydromethylpropyl cellulose, hydroxypropyl
cellulose, hydroxymethyl cellulose or hydroxyethyl
cellulose, cellulose alkyl carboxylates such as
carboxymethyl cellulose and carboxyethyl cellulose,
and alkali metal salts of cellulose alkyl
carboxylates, such as sodium carboxymethyl
cellulose and sodium carboxyethyl cellulose, or
acrylic acid homo- or copolymers or alkali metal
salts thereof.
It is to be understood that other known
hydrocolloids may be employed in the present
invention, including, for example, gum acacia,
carrageenan, guar gum, gum tragacanth, gum xanthan,
pectin, ammonium or sodium alginate or mixtures
thereof.
3C Preferred hydrocolloids are a mixture of
gelatin and sodium carboxymethyl cellulose,
carrageenan and/or sodium alginate wherein the gelatin
is present in an amount within the range of from
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about 2 to about 27% by weight and preferably from
about 10 to about 22% by weight of the
hydrocolloid mixture and the sodium carboxymethyl
cellulose, carrageenan and/or sodium alginate are
present in an amount within the range of fro~
about 2 to about 27% by weight and preferably from
about 10 to about 22% by weight of the hydrocolloid
mixture.
The ointment base suitable for use herein
may comprise any conventional ointment formulation
suitable for use in the oral cavity, such as
disclosed in Remington's "Pharmaceutical Sciences,"
Sixteenth Edition (Mack Publishing Co., Pa.).
Preferred ointment base formulations are set out in
U. S. Patent Nos. 3,029,183 and 2,628,187 and
comprise mineral oil containing a thickening agent
dispersed therein. The thickening agent will be
present in an amount of from about 0.25 to about
50% of the combined weight of mineral oil and
thickening agent.
The oils which may be used and which are
embraced within the term "mineral oil" as used
herein are the oils whlch are liquid at any
temperature in the range from 0C to 60C and
which are essentially hydrocarbons occurring in
mineral oil, their distillates and their cracked
or polymerized derivatives, an example of the last
being polybutene which includes the polymers of
butylene and its isomers. The mineral oil may be
of any desired character or viscoity, from one
which is a thin liquid to one which is so thick
that it does not flow at ordinary temperature
(20C)
Thickening (gelling) agents utilizable for
dispersion in the mineral oil include, inter alia
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SA51
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paraffin wax, amorphous wax (e.g. microcrystalline
wax), ozokerite, animal waxes (e.g. beeswax),
vegetable waxes (e.g. castor wax), and hydrocarbon
polymers (e.g. polymers of ethylene having an
average molecular weight varying from 3,500 to
26,000 and polyisobutylene of a high molecular
weight). The preferred thickening agent is
polyethylene having a molecular weight of at least
3,500.
A preferred ointment base formulation
comprises mineral oil containing polyethylene
having a molecular weight of at least 3,500. An
example of such an ointment is Plastibase 50W
(distributed by E. R. Sguibb & Sons, Inc.).
Preferred ointment formulations of the
invention are set out below.
Mg/ointment
Ingredient formulation -
20 Medicament 0.05 to 5
(Triamcinolone acetonide 0.05 to 5)
Pullulan 16.7 to 21.6
Hydrophilic polymer 15 to 55
(sodium carboxymethyl cellulose,
carrageenan and/or sodium alginate (10 to 22
and gelatin) 10 to 22)
Plastibase 50W 44 to 54
The ointment formulation of the invention
may be prepared by employing conventional
ointment formulating and processing techniques.
The active ingredient, pullulan and hydrocolloid
are added to the ointment vehicle and the mixture
1 31 3620
SA51
-13-
is mixed according to known procedures to prepare a
homogeneous ointment formulation.
The oral formulations of the lnvention will
be in the form of homogeneous pastes and will
retain their homogeneity without bleeding upon
prolonged storage. Moreover, as will be shown in
the Examples, the oral formulations of this
invention have excellent oral adhesiveness. Upon
application of the oral formulations of this
invention to the oral cavity, the formulations are
retained for prolonged periods, keeping their
original shape at the site of application even
after being heated by body temperature, and
moistened with saliva. Accordingly, the oral
formulations of the invention will maintain its
pharmacological efficacy at the site of application
without being transferred to other locations in the
oral cavity.
1313620
SA51
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The following working Examples represent
preferred embodiments of ~he present in~ention.
Unless otherwise indicated, all temperatures are
xpressed in degrees C~ntigrade.
Examples l and 2
Oral steroid ointment formulations in
accordance with the present invention having the
following composition were prepared as described
below.
Parts by Weight
Ingredient Ex. 1 Ex. 2
Triamcinolone acetonide 0.1 0.1
15 Hydrocolloid (sodium carboxy-
methylcellulose and gelatin,
50-50) 33.~ 25
Pullulan 16.7 12.5
Plastibase 50W ointment
[mineral oil-95%
polyethylene (M.W. 21,000 -
5%)] 49.8 62.4
The sodium carboxymethyl cellulose,
gelatin, pullulan and ointment were kneaded
together until a substantially homogeneous
ointment was obtained. Thereafter, triamcinolone
acetonide was added with thorough mixing until a
homogeneous ointment paste was obtained.
1 3 1 3~20
SA51
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Example 3
An oral ointment formulation of the
following composition was prepared following the
procedure of Example 1 except carrageenan was
employed as the hydrocolloid.
Inqredient Parts by Weight
Triamcinolone acetonide 0.1
Hydrocolloid (carrageenan
and gelatin, 50-50) 33.4
Pullulan 16.7
(Plastibase 50W ointment)49.8
Examples 4 and 5
Oral ointment formulations of the following
compositions were prepared following the procedure
similar to that described in Example 1 except that
sodium alginate was employed as the hydrocolloid.
Parts by Weight
Inqredient Ex. 4 Ex. 5
Triamcinolone acetonide 0.1 0.1
Hydrocolloid [sodium
alginate and gelatin (50-50)] 33.4 25
Pullulan 16.7 12.5
Plastibase 50W ointment 49.8 62.4
The adhesiveness and disintegration
properties of the oral ointments prepared in the
above examples were determined employing the
following procedures.
Adhesiveness: A 100 mg sample was placed
between two plastic plates of 3 cm in diameter.
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SA51
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The sample was spread to a film of 2 cm in
diameter on one plastic plate and then sandwiched
between the plastic plates. The two plates were
stretched and the critical tearing force at the
leaving instance (g/cm2) was determined.
Disintegration: A 200 mg sample (1 x 1
cm2) was placed at the periphery of a plastic
plate having a diameter of 12 cm. The plastic
plate was dipped into water at 37C and rotated at
300 rpm in water. The period of time at which 2/5
of the sample remained on the plastic plate was
determined.
Results: Following are the results of
these samples:
Ex. Adhesiveness Disintegration
No _ (q/cm )(min.)
1 88 45
2 68 45
3 83 40
4 77 40
67 35
The above results show that the oral
formulations of this invention have good adhesive
strength, and high disintegration resistance as
seen from the fact that they keep their original
shape for a substantial period.
