FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION

OROMUCOSAL SOLUTION FOR THE TREATMENT OF ULCERATING ORAL LESIONS.

2. APPLICANT (S)

(a) NAME: LINCOLN PHARMACEUTICALS LIMITED
(b) NATIONALITY: an Indian Company
(c) ADDRESS: Nirav complex, Opp Navrang High School,
Naranpura, Ahmedabad-380014.
Gujarat State, India.

3. PREMABLE TO THE DESCRIPTION

þ PROVISIONAL

The following specification describes the invention.

COMPLETE

The following specification particularly describes the invention and the manner in which it is to be performed.

The present invention relates to the formulation of an Oromucosal Solution for the treatment of ulcerating oral lesions.

Background of the Invention
An Aphthous ulcer, also known as a canker sore, is a type of oral ulcer, which is a painful open sore inside the mouth or upper throat caused by a break in the mucous membrane. It is also known as aphthous stomatitis, or Sutton’s Disease, especially in the case of major, multiple or recurring ulcers. Aphthous ulcers may be caused by citrus fruits, stress, fatigue, lack of sleep, illness, physical trauma, hormonal changes, menstruation, sudden weight loss, food allergies, immune system reactions, deficiency of vitamins, folic acid etc. Treatment of Canker sores till date involves the use of corticosteroids, silver nitrates, Amlexanox. But each of them have their own limitations. Corticosteroids have severe side-effects, silver nitrates reduce the pain but does not decrease the healing time, while Amlexanox is more effective at the prodromal stage.
Local anaesthetics can be topically applied to Canker sores to relieve the patient from the pain. Clinical local anaesthetics belong to either aminoamide or aminoester class or eugenol derivatives of local anaesthetics. However, as esters tend to produce allergic reactions, aminoamide class and eugenol derivatives of local anaesthetics are preferred. The aminoamide class includes, Lignocaine, Bupivacaine, Oxetacaine, Prilocaine, Dibucaine, Dyclonine, Pramoxine and Articaine while the eugenol derivatives include Eugenol, Isoeugenol and Methyleugenol. These local anaesthetics are usually weak bases and so are formulated as hydrochloride salts to render them water-soluble. Local anaesthetic drugs act mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is inhibited.
In US patent 6429228 B1, a local anesthetic for external use has been described by blending an active ingredient selected from lidocaine or prilocaine, pharmaceutically acceptable salts, a percutaneous absorption accelerator, ethanol and/or isopropyl alcohol and water which is conveniently applicable to a broad skin surface and which is excellent in percutaneous absorption, quick efficacy as well as has excellent stability.
In US patent application 2007/0110689, an oral anaesthetic gel is described which is palatable and can be used on the mucosal surface, containing an anaesthetic in a transdermal gel base having added flavoring with a bitterness suppressant where the gel base is preferably pluronic gel and the anaesthetic is preferably lignocaine.
In JP 9095456 (A), a medicine for stomatitis is described containing dibucaine hydrochloride as a local anaesthetic along with calcium carboxymethylcellulose, carboxyvinyl polymer, sodium carboxymethylcellulose, a microbicidal agent and an anti-inflammatory agent.
US patent 4005191 describes a topical ointment composition containing a mixture of non-systemic bases, a lanolin base carrier material, a hydrophilic ointment carrier material and optionally a compound having anaesthetic properties selected from, dibucaine, benzocaine, lidocaine, pramoxine hydrochloride etc. However, the preferable anaesthetic is dibucaine.
International patent application WO2006/096914 A1 discloses a synergistic combination of a topical anaesthetic and wound barrier forming agent capable of providing extended analgesia of ‘significant open wounds’ in which conventional management alternatives are impractical, unaffordable or otherwise unavailable.
In international patent application WO 2009/043134 A1, an oral rinse formulation for the prophylaxis or treatment of mucositis or stomatitis has been described. It contains a corticosteroid, an anti-histamine, a topical anaesthetic and an anti-fungal antibiotic agent.
Debridement is the process of removing non-living tissue from pressure ulcers, burns and other wounds. In this process the dead tissue is removed so that the remaining living tissue can adequately heal. The four major debridement techniques are surgical, mechanical, chemical and autolytic. Surgical debridement involves cutting the dead tissue using scissors or scalpel. Mechanical debridement involves pulling off the dead tissue by moistening it leading to the painful removal of some living tissues along with dead ones. Chemical debridement makes use of enzymes to dissolve the necrotic tissues. Autolytic debridement utilizes the body’s ability to dissolve the dead tissue slowly. 3% H2O2 is used medically for cleaning wounds and removing dead tissue. Peroxide stops wound bleeding/ oozing from small blood vessels. But these peroxide solutions are not suitable for ingestion. So an alternative debriding agent is required to be used for treating ulcerating oral lesions.
Moreover, many local anaesthetics are available as injectables, dermal patches, intravenous injection, intravenous infusion, nasal spray, oral gel, oral liquid, topical gel, topical liquid, topical patch, and topical aerosol spray.
However, the available remedies for treatment of ulcerating oral lesions usually contain only a local anaesthetic which just provides temporary relief from the pain by numbing the nerves. So a new formulation is required which along with providing relief from pain also speeds up the healing process.

Objects of the Invention:
The main object of the invention is to provide an anaesthetic and debriding agent in the form of an oromucosal solution, effective in the treatment of ulcerating oral mucosal lesions observed in Aphthous Stomatitis (Canker Sores).
Another object of this invention is to completely stop oral ulcer pain, seal damaged oral mucosal tissues and aid the natural healing processes within a short period of time after application.
Still another object of the invention is its use as an antiseptic thus preventing the irritated area from getting infected.

Summary of the Invention:
The present invention discloses a formulation which is liquid, topical, containing a local anaesthetic agent and a debriding agent used for treating ulcerating oral mucosal lesions commonly referred to as Canker Sore, Aphthous ulcers or oral ulcers. The local anaesthetic agent used is one among lignocaine, bupivacaine, oxetacaine, prilocaine, dibucaine, dyclonine hydrochloride, pramoxine hydrochloride, articaine, eugenol, isoeugenol and methyleugenol and the debriding agent used is concentrated sulfuric acid. The chemical and physical properties of this formulation are particularly beneficial whenever dental or medical procedure in the mouth requires controlled, limited debridement of necrotic or damaged tissues.

Detailed Description:
The nature of the invention and the manner in which it is performed is clearly described in the specification. The invention has various components and they are clearly described in the following pages of the provisional specification.
The present invention relates to an oromucosal solution comprising of a local anaesthetic and a debriding agent. This oromucosal solution is used for treating ulcers occurring in the mouth as lesions commonly referred to as Canker Sore, Aphthous ulcers or oral ulcers.
The local anaesthetic is selected from lignocaine, bupivacaine, prilocaine, oxetacaine, dibucaine, dyclonine hydrochloride, pramoxine hydrochloride, articaine, eugenol, isoeugenol and methyleugenol. The anaesthetic relieves the patient from the itching, burning and pain caused by skin inflammations. This is done by blocking the sodium (Na+) channels in the cell membrane. This causes the alteration in the depolarization of neurons. Due to this the neurons become numb limiting their ability to transmit the action potential. However, excess concentration of an anaesthetic may affect the cardiovascular and/or the central nervous system. Overdose symptoms may include uneven heartbeats, seizure (convulsions), coma, slowed breathing or respiratory failure.

Lignocaine also known as lidocaine, having the molecular formula C14H22N2O,

is a common local anaesthetic and antiarrhythmic drug which is used topically to relieve itching, burning and pain caused by skin inflammations. It is also injected as a dental anaesthetic and used in minor surgeries. It is the first amino amide type local anaesthetic synthesized under the name xylocaine in 1943. It is prepared by reacting 2, 6-xylidine with chloroacetylchloride. The product thus obtained is reacted with diethylamine thus producing lignocaine.
Bupivacaine, having the molecular formulaC18H28N2O, is a local anaesthetic drug belonging to the aminoamide group, which is used for infiltration, nerve block, epidural and intrathecal anaesthesia. It is also commonly injected to surgical wound sites to reduce pain for up to 20 hours after the surgery. Sometimes, bupivacaine is co-administered with epinephrine to prolong the duration of its action.
Oxetacaine, also known as oxethazaine, having the molecular formula, C28H41N3O3, is a potent local anaesthetic, administered orally for the relief of pain associated with peptic ulcer disease or esophagitis. It is also used topically in the management of hemorrhoid pain. Unlike most anaesthetics, oxetacaine is active even in strongly acidic conditions.
Prilocaine, having the molecular formula, C13H20N2O, is a local anaesthesia of the aminoamide group. In its injectable form, it is often used in dentistry. It is also often combined with lignocaine as a preparation for dermal anaesthesia (EMLA), for treatment of conditions like paresthesia. As it has low cardiac toxicity, it is commonly used for intravenous regional anaesthesia (IVRA).
Dibucaine, also known as Cinchocaine, having the molecular formula, C20H29N3O2, is an aminoamide local anaesthetic. It is the active ingredient in some topical hemorrhoid creams such as Proctosedyl. It is also a component of the veterinary drug Somulose, used for euthanasia of horses and cattle.
Dyclonine, usually available as Dyclonine hydrochloride, having the molecular formula C18H27NO2, is an aminoamide local anaesthetic. It is an oral anaesthetic found in Sucrets, an over the counter throat lozenge. It is also found in some varieties of the Cepacol sore throat spray.
Pramoxine, also known as Pramocaine, having the molecular formula C17H27NO3, is a topical local anaesthetic used as an antipruritic. It is used to relieve pain and itching caused by conditions such as sunburn or other minor burns, insect bites or stings, poison ivy, poison oak and minor cuts and scratches. Pramocaine and dibucaine are also common ingredients in over the counter hemorrhoid preparations.
Articaine, having the molecular formula, C13H20N2O3S, is a dental local anaesthetic, having an aminoamide structure with a thiophene ring instead of a benzene ring. It was first synthesized in 1969 and was then known as carticaine. Like other local anaesthetics, articaine causes a transient and completely reversible state of anaesthesia.
Eugenol, having the molecular formula, C10H12O2, is a member of the phenylpropanoids class of chemical compounds. It is a clear to pale yellow oily liquid extracted from certain essential oils especially from clove oil, nutmeg, cinnamon, and bay leaf. It is slightly soluble in water and soluble in organic solvents. It is used in perfumeries, flavorings, essential oils and in medicine as a local antiseptic and anaesthetic.
Isoeugenol, having the molecular formula, C10H13O2, is used in manufacturing perfumeries, essential oils giving an odour similar to clove, spicy, sweet, woody, in medicine as a local antiseptic and analgesic as well as in the manufacture of vanillin.
Methyleugenol is a colourless to pale yellow oily liquid having a delicate clover carnation odour and a bitter burning taste. It is used as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish and ice cream. Methyleugenol has been used as an anaesthetic in rodents. It is also used as an insect attractant in combination with insecticides.
The debriding agent used in this formulation is concentrated sulfuric acid. The solvent used for dissolving the anaesthetic is preferably a hydroalcoholic solvent selected from purified water, ethyl alcohol, PEG 400, propylene glycol, sorbitol and others
Along with a local anaesthetic and a debriding agent, the formulation contains chlorocresol as an antiseptic as well as a preservative; sucralose as a zero-calorie sugar substitute which is stable under heat and a wide range of pH conditions; aspartame as an artificial non-saccharide sweetener; solvents as a means of improving smoothness, providing lubrication and as a humectant; mixed fruit flavour to make the oromucosal solution palatable and purified water. These ingredients are mixed together to produce an oromucosal solution.
The formulation of the present invention comprises of 1.0 to 20.0%W/V local anaesthetic; 5.0 to 75.0%W/V debriding agent; 0.075 to0.8%W/V chlorocresol; 0.1 to 0.8%W/V sucralose; 0.01 to 1.0%W/V aspartame; 0.05 to 3.0%W/V mix fruit flavour; 5.0 to 75.0%W/V solvents and purified water quantity sufficient. The pH of the formulation should be in the range of 0.5 to 4.0
The formulation of the present invention preferably comprises of 5%W/V local anaesthetic; 50%W/V concentrated sulfuric acid; 0.1%W/V chlorocresol; 0.5%W/V sucralose; 0.5%W/V aspartame; 15%W/V solvents; 1%W/V mix fruit flavour; quantity sufficient purified water. The pH of the solution should preferably be 1.5.
A process is developed to prepare the said oromucosal solution formulation comprising an anaesthetic and sulfuric acid as the debriding agent. The process for preparation of oromucosal solution is as per the following steps:
1. The local anaesthetic is dissolved in a hydroalcoholic solvent.
2. Aspartame, sucralose and chlorocresol are added in the above solution.
3. The debriding agent concentrated sulfuric acid is slowly added in the above solution with constant stirring.
4. Then mix fruit flavour is added in the above mixture.
5. The volume is finally made up to 100% with purified water.
6. The pH of the solution is measured.
The present invention can be more specifically explained with reference to the following examples.
Example 1:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Lignocaine : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as per the following steps:
1. Dissolve lignocaine in a hydroalcoholic solvent.
2. Add aspartame, sucralose and chlorocresol in the above solution.
3. Slowly add debriding agent concentrated sulfuric acid in the above solution with constant stirring.
4. Then add mix fruit flavour in the above mixture.
5. Finally make up the volume to 100% with purified water.
6. Measure the pH of the solution which should be between 0.5-4.

Example 2:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Bupivacaine : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Bupivacaine.

Example 3:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Oxetacaine : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Oxetacaine.

Example 4:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Prilocaine : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Prilocaine.

Example 5:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Dibucaine : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Dibucaine.

Example 6:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Dyclonine hydrochloride : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Dyclonine hydrochloride.

Example 7:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Pramoxine hydrochloride : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Pramoxine hydrochloride.

Example 8:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Articaine : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Articaine.

Example 9:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Eugenol : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Eugenol.
Example 10:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Isoeugenol : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Isoeugenol.
Example 11:
The oromucosal solution for the treatment of ulcerating oral lesions comprises of
1. Methyleugenol : 1.0 to 20%W/V
2. Conc. Sulfuric acid : 5.0 to 75.0%W/V
3. Chlorocresol : 0.075 to 0.8%W/V
4. Sucralose : 0.1 to 0.8%W/V
5. Aspartame : 0.01 to 1.0%W/V
6. Mix Fruit Flavour : 0.05 to 3.0%W/V
7. Solvents : 5.0 to 75.0%W/V
8. Purified Water : Q.S.
The process for preparation of oromucosal solution is as described in Example 1 substituting Lignocaine with Methyleugenol.

Method of application:
The method for application of the oromucosal solution on the ulcerating oral lesions is as per the following steps:
1. Pour 1-2 drops of the oromucosal solution on a cotton bud.
2. Apply the cotton bud immediately on the affected area.
3. Keep for 2-3 seconds.
4. Remove the cotton bud.
The main advantage of using the oromucosal solution on ulcerating oral lesions is that immediately on application of the oromucosal solution, the debridement of the damaged tissues will begin causing their removal. No pain will be experienced during this process due to the presence of the local anaesthetic. Thus the application of the oromucosal solution completely stops oral ulcer pain and speeds up the healing process. The presence of chlorocresol prevents the irritated area from getting infected. Moreover, the formulation contains sweetening agents which helps to decrease the dental plaques and tooth decay.

.