WO2004056357A1

WO2004056357A1 - Composition comprising diclofenac for treating otic pain and inflammation

Info

Publication number: WO2004056357A1
Application number: PCT/IN2003/000381
Authority: WO
Inventors: Deepak Bahri
Original assignee: Deepak Bahri
Priority date: 2002-12-20
Filing date: 2003-12-04
Publication date: 2004-07-08
Also published as: AU2003303191A1

Abstract

A synergistic storage stable composition for use in the treatment of otic pain and inflammation is disclosed. The composition comprises from 0.10 to 10 % by wt of said composition a pharmaceutically acceptable salt of ortho-(2,6-dichlorophenyl)aminophenylacetic acid, from 0.1 to 10 % by wt of pharmaceutically acceptable salt of ethylenediamine tetraacetic acid and up to 80 % by wt of a mixture of propylene glycol and water, and the balance if any, consisting of conventional additives such as herein described. The composition is prepared by mixing the ingredients.

Description

COMPOSITION COMPRISING DICLOFENAC FOR TREATING OTIC PAIN AND INFLAMMATION

FIELD OF THE INVENTION

The present invention relates to a composition for use in the treatment of otic pain and inflammation. More particularly, the present invention relates to a synergistic composition based on ortho-(2,6-dichlorophenyhl)- aminophenylacetic acid for use in the treatment of otic pain and inflammation. The present invention also relates to a method for preparing a composition for use in the treatment of otic pain and inflammation and use of such composition in the treatment of otic pain and inflammation.

BACKGROUND OF THE INVENTION

Ortho-(2,6-dichlorophenyl)-aminophenylacetic acid, and its pharmaceutically acceptable salts are non-steroidal anti-inflammatory compounds useful in the treatment of pain and inflammation. Sodium ortho-(2,6-dichlorophenyl)- aminophenyl acetate, also commonly known as Diclofenac sodium has been shown for example in pharmacological studies to posses potent anti-inflammatory and analgesic properties.

While the exact mode of action of Diclofenac and other NSAIDs is not known for certainty, these agents are believed to inhibit inflammation by inhibiting the formation of prostaglandins in inflamed tissue [(Vane JR Inhibilion of prostaglandin synthesis as a mechanism of action for aspirin like drugs. Nature (New Biol), 1971, 231, 232-235)]. A large number of eicosanoids have been reported in the inflamed ear, and there is evidence to believe that ear inflammation has the same underlying pathology as inflammation at other sites. [(Devillier P Pharmacology of nonsteroidal anti-inflammatory drugs and ENT pathology. Presse Med. 2001, 30(39-40 Pt 2): 70- m

Diclofenac has been approved for use as a tablet (conventional release) and as a SR form. It is also available as an injection and as eye drops. Most of its use is as an anti-inflammatory agent. However, in the eye it is used to maintain intraoperative mydriasis, since manipulation of the iris causes prostaglandin release and miosis. Diclofenac sodium, in the form of a gel has been approved for the treatment of actinic keratosis, a pre-cancerous skin condition caused by over exposure to the sun. Age, sun exposure and fair skin are risk factors for the development of actinic keratosis, which if left untreated may develop into squamous cell carcinoma. The drug is available as the sodium and as the potassium salts.

Anti-inflammatory drugs like ketoprofen, nimesulide or Diclofenac and analgesics like paracetamol have been used to treat pain and inflammation in ENT practice [(Coscarelli S. et al; A comparison of nimesulide and ketoprofen in the prevention and treatment of painful postoperative inflammatory complications of ear, nose and throat surgery. Drugs 1993; 46 Suppl 1:174-6. Antonelli A et al; The treatment of ENT phlogosis; Seaprose S vs Nimesulide. Ada Otorhinolaryngol Ital 1993; 13, Suppl 39: 1-16, Dommerby H and Rasmussen OR Diclofenac (Voltaren). Pain relieving effect after fonsillectomy. Ada Otolargymgol 19 4, 9R(l-2) ^~ 185-192)]

Diclofenac is a potent inhibitor of COX 1 and COX II enzymes, and to some extent it inhibits the enzyme Lipooxygenase. It inhibits the formation of both prostaglandins and leukotrienes. Oral Diclofenac is used to prevent and treat inflammation and topical diclofenac is used to treat ophthalmic inflammation (Mester U, et al, A comparison of two different formulations of diclofenac sodium 0.1% in the treatment of inflammation following cataract-intraocular lens surgery. Drugs R D 2002; 3(3): 143-51, Rossetti L, et al, Effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of cystoid macular edema after cataract surgery. J Cataract Refract Surg. 1996; 22 Suppl 1: 794-9.) Cyclooxygenase activity, is specifically inhibited by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). These agents thus reduce the synthesis of prostaglandins and other metabolites of unsaturated fatty acids of the cellular membrane, mainly arachidonic acid. Both the systemic and intrathecal actions of NSAIDs can alter the post injury hyperalgesic state. Their peripheral action is indicative of the role played by prostaglandins at the site of injury with sensitization of nerve terminals. But many animal studies suggest that the antinociceptive effect of NSAIDs includes a central component related to NMDA-receptor-induced activation of the NO system which triggers the prostaglandin releasing systems in the face of persistent small afferent input generated by peripheral injury and inflammation. NSAIDs show certain selectivity in their actions. This could be related to their respective potential for inhibiting the expression of the phospholipase- A2 and cyclo-oxygenase enzymes. The inhibition of the COX enzyme by aspirin is due to the irreversible acetylation of cyclooxygenase. In contrast, other NSAIDs such as indomethacin and ibuprofen produce reversible cyclooxygenase inhibition by competing with the substrate arachidonic acid for the active site of the enzyme. The potency of NSAIDs against either COX enzyme can be expressed as the ratio of their respective IC50 and the COX-2/COX-1.

Ethylene diamine tetracetic acid has been demonstrated to be compatible with diclofenac sodium and the same has been used as taught in the US Patent Nos. 4,230,724 and 4,960,799 as a stabilizing agent.

Buffers based on combinations of phosphate salts of sodium are also compatible with diclofeanc as taught in US Patent No. 4,960,799.

In US Patent No. 4,960,799, Benzalkonium chloride has been cited as a preservative for solutions of Diclofenac. The active pharmaceutical ingredient Diclofenac is poorly soluble in water and hence mixtures of proplylene glycol and water are used to dissolve the drug. In US Patent No. 4,960,799 propylene glycol is used as a solubilizer for diclofenac. SUMMARY OF THE INVENTION The composition of the present invention is a storage stable aqueous substantially isotonic solution of a pharmaceutically acceptable salt of ortho-(2,6- dichlorophenyl)- aminophenylacetic acid. The composition ideally has a pH of between about 6.0 to 8.0.

Accordingly, the present invention provides a composition for use in the treatment of otic pain and inflammation which comprises from 0.10 to 10 % by wt of said composition a pharmaceutically acceptable salt of ortho-(2,6- dichlorophenyl)- aminophenylacetic acid, from 0.1 to 10 % by wt of pharmaceutically acceptable salt of ethylenediamine tetraacetic acid and up to 80 % by wt of a mixture of propylene glycol and water, and the balance if any, consisting of conventional additives such as herein described.

In a preferred embodiment, said conventional additive comprises of one or more of a pharmaceutically acceptable buffer and a pharmaceutically acceptable bacteriostat.

In an embodiment of the invention, said pharmaceutically acceptable buffer is present in an amount of from 0.5 to 10 % by wt of said composition.

In a preferred embodiment, said pharmaceutically acceptable bacteriostat is present in an amount of from 0.01 to about 5.0 % by wt.

In another preferred embodiment, the pharmaceutically acceptable salt is a sodium salt, more preferably, a disodium salt. In an embodiment of the invention, said buffer is selected from sodium phosphate and sodium dihydrogen phosphate dihydrate.

Preferably, said bacteriostat is selected from the group consisting of benzalkonium chloride, benzyl alcohol or sodium metabisulphite. The present invention also provides a method for the preparation of a composition for use in the treatment of otic pain and inflammation which comprises mixing in any known manner from 0.10 to 10 % by wt a pharmaceutically acceptable salt of ortho-(2,6- dichlorophenyl)-aminophenylacetic acid, from 0.1 to 10 % by wt a pharmaceutically acceptable salt of ethyl enediamine tetraacetic acid with up to 80 % by wt of a mixture of propylene glycol and water, and the balance if any, consisting of conventional additives such as herein described.

In a preferred embodiment, the composition is prepared under stirring at a temperature ranging from ambient to from 10°C and 40°C.

Finally, the present invention also provides a method for the treatment or control of otic pain and inflammation in a mammal comprising topically applying to the ear of said mammal, an effective amount of a composition comprising of from 0.10 to 10 % by wt of said composition a pharmaceutically acceptable salt of ortho-(2,6- dichlorophenyl)-aminophenylacetic acid, from 0.1 to 10 % by wt of pharmaceutically acceptable salt of ethylenediamine tetraacetic acid and up to 80 % by wt of a mixture of propylene glycol and water, and the balance if any, consisting of conventional additives such as herein described.

The amount of solution applied to the ear of the mammal in need of the same will generally be between about 0.02 and about 0.2 ml per ear per application, with generally between 1 and 12 applications per day depending upon the type and the severity of the ear inflammation.

Conventionally ENT inflammation has been treated with either oral

NSAIDs or topical steroids. Orally administered NSAIDs have significant toxicity on the gastrointestinal mucosa, the tracheobronchial tree and the kidneys. Steroids are notorious for suppressing immunity and may cause an establishment of an infection in hitherto noninfected ears, or lead to exacerbation of a pre-existing infection.

Topical NSAIDs are meant to overcome this problem. The relatively low dose of the drug instilled in the ear precludes the possibility of systemic side effects. The direct application of the drug to the inflamed tissue ensures higher bioavailability at the site of inflammation. As it is, diclofenac has been demonstrated to be absorbed from the mucosa of the eye, and the skin. DETAILED DESCRIPTION OF THE INVENTION

The invention, inter alia, relates to the development of storage stable solutions of Sodium ortho-(2,6-dichlorophenyl)-aminophenylacectate, in an isotonic form, with a pH that is compatible to that available physiologically in the ear. In a preferred embodiment, each ml of the solution comprises:. a) about 0.10 to about 10.0 mg of pharmaceutically acceptable salt of ortho- (2,6- dichlorophenlyl)-aminophenylacetic acid b) about 0.1 to about 10 mg of pharmaceutically acceptable salt of ethylenediamine tetracetic acid. c) About 0.5 mg to about 10 mg of pharmaceutically acceptable buffer d) About 0.01 to about 5.0 mg of a pharmaceutically acceptable bacteriostat e) The above ingredients are dissolved in a mixture of propylene glycol and water in ratios varying from about 9.5: 0.5 to about 0.5 : 9.5

Suitability of individual ingredients for developing the formulations was based a number of parameters. In case of the active pharmaceutical ingredient ortho- (2,6-dichlorophenyl)-aminophenylacetic acid, two salts are commonly used, the sodium and the potassium salt. The sodium salt is the forerunner, and has been used in a variety of formulations such as conventional tablets, sustained release tablets, eye drops, injections, and topical gels. For this reason the choice salt for the development was the sodium salt.

Ethylenediamine tetra acetic acid (disodium salt) is a commonly used pharmaceutical agent for stabilizing many drugs including diclofenac. It has been demonstrated to increase the stability of solutions of diclofenac even in the conditions of elevated temperature.

Buffering agents used for preparations of diclofenac include sodium phosphate/sodium dihydrogen phosphate dihydrate, tromethamine. In the present invention the phosphate salts of sodium have been chosen as buffers. A variety of preservatives have been used for ear drops in general and many have been tested and found to be compatible with diclofenac. Thus sodium metabisulphite, benzyl alcohol, and benzalkonium chloride are used to preserve solutions of diclofenac. The present invention will now be described with reference to the following Examples. The following examples are merely illustrative of the present invention and they should not considered as limiting the scope of the invention in any way, as these examples and other equivalents there of will become apparent to those versed in the art in light of the present disclosure. EXAMPLE 1 Preparation of the composition

To a 14 litre reaction vessel was added 10.5 gm of diclofenac sodium in 2500 ml of propylene glycol with continuous stirring with application of slight heat. Cool to room temperature (A).

Sodium edetate, benzalkonium chloride, sodium metabisulphite were mixed in 200 ml water with continuous stirring with application of slight heat, followed by cooling to room temperature (B).

(A) and (B) were mixed with continuous stirring and the volume was made up to 10 litres with propylene glycol. The pH was adjusted to 7.0. The solution was kept overnight.

The pH was rechecked and adjusted to 7.0 with sodium hydroxide before filling.

Sodium ortho-(2,6-dichlorophenyl)-aminophenylacetate BP 10.5 gm

Disodium ethylenediamine tetraacetate BP 1.0 gm

Propylene Glycol BP 9800 ml

Sodium metabisulphite BP 10.0 gm

Benzalkonium chloride (50%) BP 2.0 gm Sodium Hydroxide BP 2.0 gm

Purified Water BP 200 ml

EXAMPLE 2

To a 14 litre reaction vessel was added 10.5 gm of diclofenac sodium in 2500 ml of propylene glycol with continuous stirring with application of slight heat.

The mixture was cooled to room temperature (A).

400 ml Benzyl alcohol was added to solution A. (B)

Sodium edetate, sodium metabisulphite were mixed in 200 ml water with continuous stirring with application of slight heat and cooled to room temperature (C). (B) and (C) were mixed with continuous stirring and the volume made up to 10 litres with propylene glycol; pH was adjusted to 7.0. Solution was kept overnight.

The pH was checked and adjusted to 7.0 with sodium hydroxide before filling.

Sodium ortho-(2,6-dichlorophenyl)-aminophenylacetate BP 10.5 gm

Disodium ethylenediamine tetraacetate BP 1.0 gm

Propylene Glycol BP 9400 ml

Sodium metabisulphate BP 10.0 gm Benzyl alcohol BP 400 ml

Sodium Hydroxide BP 2.0 gm

Purified Water BP 200 ml

EXAMPLE 3 To a 14 litre reaction vessel, 10.5 gm of diclofenac sodium was added in

2500 ml of propylene glycol with continuous stirring with application of slight heat followed by cooling to room temperature (A).

Sodium edetate, benzalkonium chloride, sodium phosphate and sodium dihydrogen phosphate dihydrate were mixed with 2000 ml water with continuous stirring with application of slight heat and cooled to room temperature (B).

(A) and (B) were mixed with continuous stirring and the volume was made up to 10 litres with propylene glycol; pH was adjusted to 7.0 . The solution was kept overnight.

The pH was rechecked and adjuste to 7.0 with sodium hydroxide before filling.

Sodium ortho-(2, 6-dichloropheny l)-aminophenylacetate BP 10.5 gm Disodium ethylenediamine tetraacetate BP 1.0 gm Propylene Glycol BP 8000 ml Sodium phosphate BP 25.3 gm

Sodium dihydrogen phosphate dihydrate BP 25 gm Benzalkonium chloride (50%) BP 2.0 gm Sodium Hydroxide BP 9.0 gm EXAMPLE 4

The following Example demonstrates the efficacy of the composition of the present invention.

Sixty-eight consecutive patients suffering from Acute otitis media, acute otitis externa or CSOM with Otitis externa were enrolled in the comparative trial.

Patients below the age of 18 or above 60 years were excluded. Other types of patients excluded were pregnant patients, those with history of acid peptic or bronchospastic disease or those with hepatic or renal impairment.

After verifying that the patients fulfilled the inclusion and exclusion criteria, they were allotted a unique case number and their anamnestic data were recorded. The patient's detailed history was noted and the patients were subjected to a detailed ENT examination. The patients were asked to rate their symptoms on a visual analogue scale of 0 to 10, representing no symptom to extremely distressing symptoms. Audiometry was performed for both air and bone conduction and their basal hearing was assessed.

On a random basis the patients were allotted to one of the two treatment groups. In group A the patients were advised Diclofenac sodium enteric coated tablets 50 mg three times day, and in Group B they were advised 3 drops of Diclofenac sodium ear drops in the affected ear three time a day. This was in addition to other therapy, oral antibiotics, antifungal and wax dissolving drops. Care was taken to avoid any medication, which contained analgesics or local anaesthetics since they would interfere with the assessment of the therapy. Patients were also provided with a rescue medication, which comprised of Ibuprofen 400 mg tablets to be taken SOS.

The patients were asked to report back after two, five and seven days and during each visit their symptoms were recorded and the ENT examination performed. On the seventh day audiometry was repeated to assess the status of hearing at the end of the therapy. There was provision to continue therapy in patients who did not find complete relief. The trial was terminated after fifty patients completed the trials.

The protocols were analyzed and the results of the patients on oral therapy and eardrops compared using the regular statistical models. Results

The controlled trial, which was conducted between May to September 2002 enrolled sixty eight patients of which fifty completed the trial. The 18 patients who dropped out did not give any reason fo r doing so, , and were lost to follow up. The anamnestic details of the patients who completed the trial are given below:

Pa itient Demography Table 1

S. No. Variable Group A Group B

1 Number 25 25

2 Males 17 19

3 Females 8 6

4 Age (Years) 34.3 ± 9.4 36.8 ± 8.5

5 Weight (Kg) 56.7 ± 12.6 52.9 ± 14.2

The diagnosis wise break up of the patients in the two groups was as shown in Table 2

Diagnosis Table 2

SS.. NNoo.. DDiiaaggnnoossiiss GGrroouupp AA Group B

1 Acute Otitis Externa 13 16

2 Acute Otitis Media 8 6

3 Chronic Suppurative 4 3 Otitis Media with Otitis Externa

Table 3 gives the details of the symptoms of the patients. The patients' symptoms were rated on a 0-10 visual analogue scale and the duration of symptoms in days recorded alongwith. The table 3 given below gives the VAS rating for each symptom and the mean duration of the symptoms is given in Table 4. The patients' reports were verified by the physician and the observations of the physician were recorded after discussion with the patient. The results of the audiometry are shown in table 5.

Symptom Score VAS Table 3

S. No. Symptom Group A Group B

Right Left Right Left

1 Pain 7.3 ± 2.1 6.5 ± 3.1 7.2 ± 2.9 6.4 ± 2.7

3 Discharge 4.3 ± 1.5 5.2 ± 1.6 5.2 ± 2.1 6.0 ± 2.7 4 Tinnitus 3.4 ±1.8 2.9 ±1.2 4.2 ±1.6 3.2 ±2.2

5 Hearing Loss 2.8 ±0.8 2.5 ±0.6 2.7 ±0.8 2.5 ±0.7

Symptom History Table 4 Duration of symptom in days

S.No. Symptom Group A Group B

Right Left Right Left

1 Pain 2.1 ±0.7 2.8 ±0.5 1.9 ±0.4 2.4 ±0.7

3 Discharge 2.0 ± 0.2 1.5 ±0.4 1.2 ±1.1 1.2 ±0.7

4 Tinnitus 5.4 ±2.8 4.6 ±1.3 5.2 ±1.9 5.2 ±2.9

5 Hearing Loss NA NA NA NA

Symptom Examination Table 5

S.No. Symptom Group A Group B

Right Left Right Left

1 Swelling (Positive) 12 11 12 13

2 Discharge (Positive) 10 12 8 10

3 Fungus (Positive) 7 8 6 7

4 Wax (Positive) 19 19 20 19

5 Tympanic Membrane 8 7 6 8 (Inflamed)

6 Mid Ear Mucosa 9 8 8 7 (Inflamed)

7 Hearing (Impaired) 7 6 6 7

8 Nose (Abnormal) 3 2

9 Throat (Abnormal) 2 2

10 Lymph Nodes (Swollen) 4 3

Effect of Therapy Table 6 A

Group A S.No. Symptom Da O Day 2 Day 5 Day 7

1 Pain 7.0 ±2.3 4.5 ±3.1 2.1 ±1.5 1.4±0.8

2 Swelling 4.8 ±1.5 3.2± 1.6 1.2 ±0.9 0.9 ±0.2 3 Tinnitus 3.1 ±1.6 2.1 ± 1.2 1.8±0.5 1.5 ±0.7

4 Blockade 2.6 ±0.7 1.5 ±0.6 1.4 ±0.6 1.4 ±0.6

Group B Table 6B

S.No. Symptom DayO Day 2 Day 5 Day 7

1. Pain 6.9 + 2.2 2.5 + 1.1 0.6 + 0.1 0.0

2. Swelling 5.8+ 1.6 1.2 + 0.6 0.4 + 0.2 0.0

3. Tinnitus 3.8+ 1.7 0.8 + 0.4 0.2 + 0.05 0.0

4. Blockade 2.6 + 0.6 0.9 + 0.3 0.3+0.1 0.0

Audiometry : Basal

Hearing Group A Group B

Right Left Right left

Impaired 7

Final

Hearing Group A Group B Right Left Right Left

Impaired 3 3 1 1

Adverse reactions Table 7

Side Effects

S. No. Symptom Group A Group B:

1. Burning 0 7

2. Tinnitus 0 0 3. Imbalance 3 2

4. Hearing Loss 0 0

5. GI Disturbance 4 0

6. Bronchial Distress 1 0

Findings

Both groups of patients were found to improve with the therapy, however the recovery with topical therapy was faster.

Symptoms Patients of both the groups had reduction in pain with the institution of therapy, however, the reduction of pain was superior with the eardrops than with tablets. The same was true for swelling tinnitus and blockade. In all the symptoms the ear drops scored significantly over the oral tablets.

Hearing Seven patients had impaired hearing in either of the ears at the beginning of the therapy. At the end of seven days only 3 people had impaired hearing in Group A

(oral therapy) and one patient had impaired hearing in the ear drop group.

Side effects The side effects in both the groups were mild and transient. Patients receiving eardrops experienced some burning after the instillation of the drops.

Imbalance was experienced by 3 patients in group A and 2 patients in Group B. Gastric distress was observed in 4 patients of Group A and none of Group B. Bronchial distress was seen in one patient receiving Diclofenac tablets but none receiving ear drops.

The side effects of the drugs were quite expected and eardrops showed more local reactions than the systemic effects seen with tablets.

Conclusions

The Global efficacy rating of the ear drops was vastly superior to that of the tablets. The ear drops were rated at 2.8 on a 0-3 scale while the tablets were rated as 2.3 on the same scale.

The present invention demonstrates that the composition of the present invention is superior to known tablets in controlling pain and inflammation of the ear.

Claims

Claims:

1. A storage stable composition for use in the treatment of otic pain and inflammation which comprises from 0.10 to 10 % by wt of said composition a pharmaceutically acceptable salt of ortho-(2,6-dichlorophenyl)-aminophenylacetic acid, from 0.1 to 10 % by wt of pharmaceutically acceptable salt of ethylenediamine tetraacetic acid and up to 80 % by wt of a mixture of propylene glycol and water, and the balance if any, consisting of conventional additives such as herein described.

2. A composition as claimed in claim 1 wherein said conventional additive comprises of one or more of a pharmaceutically acceptable buffer and a pharmaceutically acceptable bacteriostat.

3. A composition as claimed in claim 1 or 2 wherein said pharmaceutically acceptable buffer is present in an amount of from 0.5 to 10 % by wt of said composition.

4. A composition as claimed in any preceding claim wherein said pharmaceutically acceptable bacteriostat is present in an amount of from 0.01 to about

5.0 % by wt.

5. A composition as claimed in any preceding claim wherein said pharmaceutically acceptable salt is a sodium salt, more preferably, a disodium salt.

6. A composition as claimed in any one of claims 2 to 5 wherein said buffer is selected from sodium phosphate and sodium dihydrogen phosphate dihydrate

7. A composition as claimed in any one of claims 2 to 6 wherein said bacteriostat is selected from the group consisting of benzalkonium chloride, benzyl alcohol or sodium metabisulphite.

8. A method for the preparation of a composition for use in the treatment of otic pain and inflammation which comprises mixing in any known manner from 0.10 to

10 % by wt a pharmaceutically acceptable salt of ortho-(2,6- dichlorophenyl)- aminophenylacetic acid, from 0.1 to 10 % by wt a pharmaceutically acceptable salt of ethylenediamine tetraacetic acid with up to 80 % by wt of a mixture of propylene glycol and water, and the balance if any, consisting of conventional additives such as herein described.

9. A method as claimed in claim 8 wherein the composition is prepared under stirring at a temperature ranging from ambient to from 10°C and 40°C.

10. A method as claimed in claim 8 or 9 wherein said conventional additive comprises of one or more of a pharmaceutically acceptable buffer and a a pharmaceutically acceptable bacteriostat.

11. A method as claimed in any one of claims 8 to 10 wherein said pharmaceutically acceptable buffer is present in an amount of from 0.5 to 10 % by wt of said composition.

12. A method as claimed in any one of claims 8 to 11 wherein said pharmaceutically acceptable bacteriostat is present in an amount of from 0.01 to about 5.0 % by wt.

13. A method as claimed in any one of claims 8 to 12 said pharmaceutically acceptable salt is a sodium salt, more preferably, a disodium salt.

14. A method as claimed in any one of claims 8 to 13 wherein said buffer is selected from sodium phosphate and sodium dihydrogen phosphate dihydrate

15. A method as claimed in any one of claims 8 to 14 wherein said bacteriostat is selected from the group consisting of benzalkonium chloride, benzyl alcohol or sodium metabisulphite.

16. A method for the treatment or control of otic pain and inflammation in a mammal comprising the topically applying to the ear of said mammal, an effective amount of the a composition comprising of from 0.10 to 10 % by wt of said composition a pharmaceutically acceptable salt of ortho-(2,6- dichlorophenyl)- aminophenylacetic acid, from 0.1 to 10 % by wt of pharmaceutically acceptable salt of ethylenediamine tetraacetic acid and up to 80 % by wt of a mixture of propylene glycol and water, and the balance if any, consisting of conventional additives such as herein described.

17. A storage stable composition for use in the treatment of otic pain and inflammation substantially as herein described with reference to the foregoing examples.

18. A method for the preparation of a storage stable composition for use in the treatment of otic pain and inflammation substantially as herein described with reference to the foregoing examples.