DESCRIPTION
FIELD OF THE INVENTION
The present invention is related to a pharmaceutical formulation
indicated for the use in oral ulcers. Present invention also discloses
5 the method by which the said invention is to be formulated to arrive at
a stable formulation. Further, the present invention is related to a
pharmaceutical formulation in gel form for applying on oral ulcers.
Preferably the active ingredient in the gel from comprises
Rebamipide. The formulation manufactured according to the process
10 disclosed according to the present invention provides a formulation
which is stable and fit for pharmaceutical use.
BACKGROUND OF THE INVENTION
An oral ulcer typically starts with a tingling or burning sensation at the
site of the future mouth ulcer. In a few days, it can progress to form a
15 red spot or bump, followed by an open ulcer. Oral ulcers are
characterized by the loss of mucosal membrane of the mouth. These
may vary as per the time period i.e. they may be acute or chronic.
They are painful and generally red or yellow. They often make eating
and drinking uncomfortable. They occur generally on the inside of the
20 lips, inside the cheeks, on the tongue, at the base of the gums or on
the roof of the mouth. The presently used medicine either orally,
• intravenously or intramuscularly, and other methods, are non-patient
compliance, bring more suffering to the patient, since the
administered drug should either absorbed or function through the
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blood flow thus often work slowly, and thus provides long course of
treatment and poor efficacy, especially in infants and young children.
Thus there is clearly as need for the formulation which works directly
at the site of action and provides immediate action without being
5 supplied systemically. The molecule of the present invention is
selected due to its efficacy and having lesser side effects.
Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, is used
for mucosal protection, healing of gastroduodenal ulcers, and
treatment of gastritis. It works by enhancing mucosal defense,
10 scavenging free radicals, and temporarily activating genes encoding
cyclooxygenase-2.
US 20100029714 discloses a rebamipide-containing aqueous
pharmaceutical*suspension which can be prepared by a simple
process and keep the dispersed fine-particle state of rebamipide
15 stable without having the fine particle agglutinated. The rebamipidecontaining
aqueous pharmaceutical suspension of the invention is
prepared by mixing polyvinyl alcohol and additionally a sodium salt
compound with rebamipide.
CN 104274402 provides medicine water suspended emulsion
20 containing rebamipide and povidone, wherein rebamipide fine
particles dispersed in the water suspended emulsion can maintain a
stable dispersed state and cannot get together; besides, the
invention also provides a method for preparing the medicine water
suspended emulsion containing rebamipide and povidone, and the
25 method for preparing the medicine water suspended emulsion
comprises the step of mixing povidone and sodium salt compound
with rebamipide.
US 8617606 discloses a hydrogel suspension which comprises
(1) an aqueous suspension of fine particles which comprises (i) at
least one compound selected from water-soluble polymers and
surfactants, (ii) an acidic aqueous solution, and (iii) an aqueous
solution containing a water-soluble salt of rebamipide; the particle
size of which is not more than 500 nm; and which is obtainable by (i)
mixing an acidic aqueous solution containing at least one compound
selected from water-soluble polymers and surfactants, and an
aqueous solution containing a water-soluble salt of rebamipide, (ii)
mixing an acidic aqueous solution, and an aqueous solution
containing a water-soluble salt of rebamipide and at least one
compound selected from water-soluble polymers and surfactants, or
(iii) mixing an acidic aqueous solution containing at least one
compound selected from water-soluble polymers and surfactants,
and an aqueous solution containing a water-soluble salt of
rebamipide and at least one compound selected from water-soluble
polymers and surfactants, and
(2) (i) hydroxypropylmethyl cellulose whose methoxyl content and
hydroxypropoxyl content are 10-40% (w/w) and 1-20% (w/w),
respectively, and whose viscosity grade (2% (w/v) aqueous solution)
is not less than 1500 mm2/s; or (ii) methyl cellulose whose methoxyl
content is 20-40% (w/w), and whose viscosity grade (2% (w/v)
aqueous solution) is not less than 1500 mm2/s.
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In mouth ulcer, the prime objective of treatment is to reduce the pain
and healing the ulcer. However, none of the above prior art discloses
the formulation for healing ulcer and reducing pain simultaneously,
along with improved drug penetration.
Thus there exists a need to develop a formulation that has both the
pain relieving property as well as ulcer healing property along with
better tissue penetration.
OBJECT OF THE PRESENT INVENTION
The object of the present invention is to provide a formulation which
is used to treat oral ulcers.
Another object of the present invention is to develop a formulation for
topical use.
Yet another object of the present invention is related to an oral gel of
rebamipide.
Another object of the present invention is to develop, a process
through which a stable product can be developed.
Another object of the present invention is to develop a formulation
providing Rebamipide with penetration enhancer so as to provide
deep tissue penetration.,
Further object of the present invention is to provide Rebamipide with
pain reliving substance for better efficacy.
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DETAILED DESCRIPTION OF THE INVENTION
Rebamipide, which means a carbostyril compound (chemical name:
2-(4-chlorobenzoylamino)-3-[2(1H)-quinolon-4-yl] propionic acid) of
the below formula, is a medicament that has a potent effect on the
treatment of gastric ulcer, acute gastritis, or gastric mucosa lesion
affected in acute exacerbation of chronic gastritis.
Rebamipide occurs as a white crystalline powder that is odorless and
has a bitter taste. It is very slightly soluble in methanol and ethanol
10 but is practically insoluble in water.
Rebamipide is known as an agent for improving both subjective and
objective symptoms of diseases such as gastric ulcer, duodenal
ulcer, gastritis and other like diseases. It has also been disclosed that
rebamipide is useful in the treatment of various other diseases, for
15 example, for the treatment a ulcerative colitis.
Rebamipide is also known for having an increasing action of goblet
cell density in the eye, an increasing action of mucus in the eye and'
an increasing action of lacrimal fluid, and it is already known as an
agent for treating dry eye.
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Useful sweetening agents include water-soluble sweetening agents
such . as, for example, monosaccharides, disaccharides and
polysaccharides; water-soluble artificial sweetening agents such as,
for example, soluble saccharin salts and the like; dipeptide based
5 sweetening agents such as L-aspartic acid derived sweetening
agents and the like or mixtures thereof. The suitable sweeteners also
include sucralose, aspartame, acesulfame potassium, neotame,
saccharin, xylitol and mixtures thereof.
The pain relieving component in the present invention can be
10 selected from aloe vera, peppermint, lemon, orange, eucalyptus, or
rosemary oils or mixture thereof.
The term "penetration enhancer" .means an increase in the
permeability of a biological membrane (i.e. skin or mucosa) to a drug,
so as to increase the rate at which the drug permeates through the
15 membrane, and an "effective amount" of an enhancer means an
amount effective to enhance penetration through the skin or mucosa
of a selected agent to a selected degree. A penetration enhancer
may be a single substance or a group of substance performing the
function of penetration enhancer. The penetration enhancer can be
20 selected, but not limited to, from Examples of penetration enhancers
include: peppermint; alcohols, such as ethanoi and isopropanol;
polyols, such as n-alkanols, limonene, terpenes, dioxolane,
propylene glycol, ethylene glycol, other glycols, and glycerol;
sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformamide,
25 methyl dodecyl sulfoxide, dimethylacetamide; esters, such as
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isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methyl
propionate, and capric/caprylic triglycerides; ketones; amides, such
as acetamides; oleates, such as triolein; various surfactants, such as
sodium lauryl sulfate; various alkanoic acids, such as caprylic acid;
5 lactam compounds, such as azone; alkanols, such as oleyl alcohol;
dialkylamino acetates, and admixtures thereof.
The gelling agent is selected from hydrophilic polymers,
monosaccharides, polysaccharides (including functionalized
polysaccharides), cyclic saccharides (including Dextrans), polyols,
10 celluloses (including cellulose, methylcelluloses, sodium
carboxymethyl cellulose, hydroxylalkylmethylcellulose, and derivative
celluloses), cremophor EL, gums (e.g., xanthan gum and the like),
polyvinyl alcohols, polyvinylpyrrolidone, polymethacrylates, polyvinyl
acetates, pectins and mixtures thereof. In certain embodiments, the
15 viscosity enhancer is preferably selected from among a
methylcellulose, Carbomer 940, polyethylene glycol, and polyvinyl
alcohol, and is more preferably methylcellulose, hydroxypropyl
methylcellulose, hydroxy! ethylcellulose, or polyvinylpyrrolidone.
The formulation manufactured as per the embodiments of the present
20 invention should be used topically and may be in the form, but not
limited to, cream, gel, ointment, lotion or the like.
The preferred embodiment according to the present invention
comprises Rebapimide, a penetration enhancer, a sweetener, a pain
reliever, gelling agent and pH adjuster.
_-^... — — ...
The invention can be formulated, but not limited to, in the following
manner:
S. No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Material Name
Rebamipide (micronized)
Carbomer 940
Polyethylene Glycol 400
Sucralose
Sodium Methyl Paraben
Sodium Propyl Paraben
Eucalyptol
Peppermint Oil
Triethanolamine
Purified Water
Label Claim
2.0% w/w
-
-
_-
i —
-
-
-
-
-
UOM
Kg
Kg
Kg
Kg
Kg
Kg
Kg
Kg
Kg
Kg"
Quantity
Required
2.00
1.70
30.00
0.05
0.10
. 0.0333
0.03
0.10
0.30
q.sto 100
kg
Procedure:-
1. Take 40.00 Kg of purified water in SS vessel and add 1.70 Kg
of Carbomer 940 under stirring to get uniform gel like mass
soak it for 4 hours.
2. Take 15.00 kg of purified water in another SS vessel and
dissolve the sodium methyl paraben and sodium propyl
paraben with continuous stirring till get dissolve. .
3. Add sucralose to step no.2 with continues stirring to get
dissolve.
4. Add the step no. 3 in to the step no.1 with continues stirring
anchor speed 40 RPM and homogenize for 5 minutes at 2800
rpm under vacuum.
5. Take 30.00 Kg of Propylene glycol in another SS vessel and
add 2.00 Kg of micronized Rebamipide stir at 50-100 RPM to
get uniform dispersion. Stir continuous for another 40^50
minutes to get uniform.
6. Add above dispersion in to step no. 4 with continuous at
anchor speed 40 RPM and homogenizer speed 2800 RPM for
5 minutes in every 10 minutes interval for 60 minutes.
7. Now adjust the pH with triethonlamine between 5.0-7.0
8. Now add Peppermint 0.100 kg and Eucalyptol 0.030 Kg to
above with continuous stirring for 10 minutes at anchor speed
30 RPM.
9. Make up the final weight up to 100.00 Kg and mix all about 60
minutes with anchor speed 30-40 RPM.
10. Check the final pH ranges between 5.0 - 7.0.

CLAIMS
We claim:
1) A topical formulation comprising rebamipide for the treatment of oral ulcer along
with pharmaceutical excipients.
2) The Rebamipide, as claimed in claim 1, is in the range of 1% w/w.to 5% w/w.
3) The quantity of rebamipide, as claimed in claim 2, is preferably 2%w/w.
4) Pharmaceutical excipients claimed in claim 1 comprise penetration enhancer,
viscosity enhancers, sweetener and preservatives.
5) Penetration enhancer claimed in claim 4 be selected from : peppermint; alcohols,
such as ethanol and isopropanol; polyols, such as n-alkanols, limonene, terpenes,
dioxolane, propylene glycol, ethylene glycol, other glycols, and glycerol; sulfoxides,
such as dimethylsulfoxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide,
dimethylacetamide; esters, such as isopropyl myristate/palmitate, ethyl acetate, butyl
acetate; methyl propionate, and capric/caprylic triglycerides; ketones; amides, such
as acetamides; oleates, such as triolein; various surfactants, such as sodium lauryl
sulfate; various alkanoic acids, such as caprylic acid; lactam compounds, such as
azone; alkanols, such as oleyl alcohol; dialkylamino acetates, and admixtures
thereof, preferably peppermint.
6) The viscosity enhancer as claimed in claim 4 is selected from among a
methylcellulose, Carbomer 940, polyethylene glycol, and polyvinyl alcohol, and is
more preferably methylcellulose, hydroxypropyl methylcellulose, hydroxyl
ethylcellulose, or polyvinylpyrrolidone, preferably Carbomer 940.
7) The sweetener, ac claimed in claim 4 is preferably sucralose.
8) Formulation claimed in claim 1 further comprises of a pain reliever.
9) The pain reliever, as claimed in claim 8 is preferably.eucalyptol.