ORAL TOPICAL AQUEOUS PHARMACEUTICAL COMPOSITIONS OF FLURBIPROFEN AND DEXPANTHENOL

Abstract

The present invention relates to stable oral topical aqueous pharmaceutical compositions comprising flurbiprofen or pharmaceutically acceptable salts thereof and dexpanthenol or pharmaceutically acceptable salts thereof. Furthermore the present invention also relates to stable oral topical aqueous pharmaceutical compositions comprising flurbiprofen or pharmaceutically acceptable salts thereof and dexpanthenol or pharmaceutically acceptable salts thereof and chlorhexidine or pharmaceutically acceptable salts thereof. More particularly, the present invention relates to stable oral topical aqueous pharmaceutical compositions of these combinations having desired levels of solubility, enhanced taste and absorption from mucosal surface, wherein the pH of the solution is between 6 and 7.

Claims

1. An oral topical aqueous pharmaceutical composition comprising: (i) flurbiprofen or pharmaceutically acceptable salts thereof; (ii) dexpanthenol or pharmaceutically acceptable salts thereof.

2. The composition according to claim 1, wherein the pH of the solution is between 6 and 7.

3. The composition according to claim 1 or 2 comprising on a weight basis, (i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof; (iii) 0.1 to 5.0% sodium hydroxide to adjust the pH of the solution to between 6 and 7.

4. The composition according to claim 1, further comprising menthol.

5. The composition according to claim 4, comprising on a weight basis, (i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof; (iii) 0.01 to 2.0% menthol

6. The composition according to claims 1 to 5 comprising on a weight basis, (i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof; (iii) 0.01 to 2.0% menthol (iv) 0.1 to 5.0% sodium hydroxide to adjust the pH of the solution to between 6 and 7.

7. The composition according to claims 1 to 6, further comprising at least one solvent in an amount of from 5.0 to 45.0% by weight of the total composition.

8. The composition according to claim 7, wherein the solvent is selected from a group comprising ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and mixtures thereof.

9. The composition according to claim 8, wherein the solvent is ethyl alcohol, glycerin and sorbitol.

10. The composition according to claims 1 to 9, further comprising at least one sweetening agent in an amount of from 0.01 to 2.0% by weight of the total composition.

11. The composition according to claim 10, wherein the sweetening agent is selected from the group comprising saccharine sodium, sorbitol, aspartame, fructose, isomalt, maltitol, maltose, mannitol, sucrose, xylitol, glycerin and their mixtures; preferably the sweetening agent is saccharine sodium.

12. The composition according to claims 1 to 11, further comprising at least one surface active agent in an amount of from 0.1 to 5.0% by weight of the total composition.

13. The composition according to claim 12, wherein the surface active agent is selected from the group comprising, polyoxyethylene castor oil derivatives, polysorbate, polyexyethylene stearates, polyoxylglycerides, glyceryl monooleate, sorbic acid, butylparaben, phospholipids and mixtures thereof; preferably the surface active agent is polyoxyethylene castor oil derivatives; more preferably polyoxyl 40 hydrogenated castor oil.

14. The composition according to claims 1 to 13, further comprising at least one preservative in an amount of from 0.01 to 0.50% by weight of the total composition.

15. The composition according to claim 14, wherein the preservative is selected from the group comprising methyl paraben, propyl paraben and salts thereof, sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene and butylated hydroxyanisole or mixtures thereof; preferably the preservatives are methyl paraben and propyl paraben.

16. The composition according to any of the preceding claims, comprising on a weight basis: (i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof; (iii) 0.01 to 2.0% menthol (iv) 0.1 to 5.0% sodium hydroxide (v) 5.0 to 20.0% sorbitol; (vi) 0.01 to 2.0% saccharine sodium; (vii) 5.0 to 25.0% glycerin; (viii) 0.1 to 5.0% polyoxyl 40 hydrogenated castor oil; (ix) 0.01 to 0.50% methyl paraben, (x) 0.01 to 0.20% propyl paraben, (xi) 5.0 to 15.0% ethyl alcohol (xii) 0.0001 to 0.001% patent blue

17. The composition according to claim 1, further comprising chlorhexidine or pharmaceutically acceptable salts thereof.

18. The composition according to claim 17 comprising on a weight basis, (i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof; (iii) 0.01 to 3.0% chlorhexidine or pharmaceutically acceptable salts thereof;

19. The composition according to claim 18, comprising on a weight basis: (i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof; (iii) 0.01 to 3.0% chlorhexidine or pharmaceutically acceptable salts thereof; (iv) 0.01 to 2.0% menthol (v) 0.1 to 5.0% sodium hydroxide (vi) 5.0 to 20.0% sorbitol; (vii) 0.01 to 2.0% saccharine sodium; (viii) 5.0 to 25.0% glycerin; (ix) 0.1 to 5.0% polyoxyl 40 hydrogenated castor oil; (x) 5.0 to 15.0% ethyl alcohol (xi) 0.0001 to 0.001% patent blue

20. The composition according to any one of the preceding claims, wherein said composition is in the form of a mouthwash, mouth rinse or spray.

21. The composition according to any one of the preceding claims, for use in the treatment of oral mucosa and oral cavity inflammations, stomatitis, aphtha, periodontal diseases and non-specific epidermal and muco-epidermal infections and inflammation.

Description

DETAILED DESCRIPTION OF INVENTION

[0018] According to the present invention, a novel oral topical aqueous pharmaceutical composition with anti-inflammatory and antiseptic activities is obtained surprisingly, which is having desired levels of solubility, enhanced taste and rapidly absorbed from the oral mucosa.

[0019] Flurbiprofen useful in accordance with this invention includes the pharmaceutically acceptable salts and esters of flurbiprofen, and further includes the conventionally used racemic mixture which comprises the S- and R-enantiomers of flurbiprofen. The topical aqueous pharmaceutical compositions of the invention comprise from 0.01 to 5.0% flurbiprofen, preferably from 0.05 to 3.0%, more preferably from 0.10 to 2.0% by weight of the total composition.

[0020] The topical aqueous pharmaceutical compositions of the invention comprise from 0.10 to 10.0% dexpanthenol or salts and esters thereof, preferably from 0.50 to 8.0%, more preferably from 1.0 to 7.5% by weight of the total composition.

[0021] The topical aqueous pharmaceutical compositions of the invention comprise an alkalizing agent to adjust the pH of the solution to pH 6-7. Adjusting the pH of the solution to about 6 to 7 pH helps to enhance the dissolution, extent of penetration into oral mucosa, especially muco-epidermal and epidermal tissue and bioavailability. It also helps to increase the solubility of flurbiprofen which is otherwise insoluble in water thus making the aqueous formulations of it difficult and may cause a blur solution. Adjusting the pH to about 6 to 7 both helps to improve the solubility of flurbiprofen, dexpanthenol and furthermore chlorhexidine and increase the rate of absorption of them from the oral mucosal surface and thus a homogenous and clear solution is also obtained.

[0022] According to this embodiment, the oral aqueous pharmaceutical composition of the present invention comprises, on a weight basis,

(i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof;
(ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof;
(iii) 0.1 to 5.0% sodium hydroxide to adjust the pH of the solution to between 6 and 7.

[0023] Suitable alkalizing agents comprise but not limited to sodium hydroxide, calcium hydroxide, diethanolamine, monoethanolamine, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dehydrate, triethanolamine and mixtures thereof. Preferably alkalizing agent is sodium hydroxide. Suitable alkalizing agents are preferably from 0.1 to 5.0%, more preferably from 1.0 to 4.0% by weight of the total composition.

[0024] In another embodiment, the topical aqueous pharmaceutical compositions of the invention comprise menthol, from 0.01 to 2.0%, preferably from 0.05 to 1.0%, more preferably from 0.1 to 0.5% by weight of the total composition. Menthol helps the composition of the present invention to improve and enhance the penetrating and spreading properties through the oral mucosal surface. It also helps to increase the solubility of the flurbiprofen and dexpanthenol and thus a homogenous and clear solution is obtained. Accordingly, menthol is used as a flavoring agent and masks the bitter taste of dexpanthenol and flurbiprofen. When other flavoring agents are used an unclear and blurry solution is obtained. The present inventors discovered that using menthol as a taste enhancer solves this problem and a clear solution is obtained as desired.

[0025] Furthermore menthol used in the formulation gives anesthetic effect at the side of administration as a result of stimulating the receptors by which cold sensation is perceived. Menthol when used with flurbiprofen and dexpanthenol, provides significant relief of pain associated with oral mucosa and oral cavity inflammations, periodontal disease and non-specific epidermal and muco-epidermal infections. Also menthol helps to mask the bad odour of the other excipients to obtain a good patient compliance when applying inside the mouth.

[0026] According to these embodiments, the oral aqueous pharmaceutical composition of the present invention comprises, on a weight basis,

(i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof;
(ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof;
(iii) 0.01 to 2.0% menthol

[0027] In a preferred embodiment, the oral aqueous pharmaceutical composition of the present invention comprises, on a weight basis,

(i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof;
(ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof;
(iii) 0.01 to 2.0% menthol
(iv) 0.1 to 5.0% sodium hydroxide to adjust the pH of the solution to between 6 and 7.

[0028] The pharmaceutical compositions according to the present invention may also comprise one or more pharmaceutically acceptable excipients. Such suitable pharmaceutically acceptable excipients comprise, but are not limited to surfactants, viscosity enhancers, flavoring agents, sweetening agents, solvents, and their mixtures. The pharmaceutical compositions according to the present invention further comprise a dye optionally.

[0029] Suitable solvents may comprise but not limited to ethyl alcohol, glycerin, sorbitol, propylene glycol, polyethylene glycol, isopropyl alcohol, purified water and mixtures thereof. Preferably ethyl alcohol, sorbitol, glycerin and purified water are used. Ethyl alcohol is also utilized as a microbiological preservative. Suitable solvents are used in an amount of from 5 to 45%, preferably from 10 to 35% by weight of the total composition.

[0030] Suitable preservatives, may include but not limited to methyl paraben, propyl paraben and salts thereof (e.g. sodium or potassium salts), sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene and butylated hydroxyanisole or mixtures thereof. Preferably the preservatives are methyl paraben and propyl paraben in an amount of 0.01 to 0.50% by weight of the total composition, more preferably in an amount of 0.01 to 0.15% by weight of the total composition.

[0031] Suitable surface active agents may comprise but not limited to polyoxyethylene castor oil derivatives, polysorbate, polyexyethylene stearates, polyoxylglycerides, glyceryl monooleate, sorbic acid, butylparaben, phospholipids and mixtures thereof. Preferably the surface active agent is polyoxyethylene castor oil derivatives, more preferably polyoxyl 40 hydrogenated castor oil. The amount of polyoxyethylene castor oil derivative is from 0.1 to 5.0%, preferably from 0.5 to 2.5% by weight of the total composition. These amounts of polyoxyethylene castor oil derivatives improve the spreading properties and minimize drying of the aqueous compositions of the present invention when it is applied inside of the mouth via spray, mouth rinse or mouthwash.

[0032] Suitable viscosity enhancers may comprise but not limited to glycerin, sodium carboxyl methyl cellulose, dextran, cellulose and derivatives, chitosan, carbomer and mixtures thereof. Preferably the viscosity enhancer is glycerin and the amount is from 5.0 to 25.0%, preferably from 10.0 to 25%, more preferably from 10.0 to 20.0% by weight of the total composition. Glycerin has also a stabilization effect when it is used in these amounts and helps the formulation to be stable over the shelf life.

[0033] Suitable flavoring agents may comprise but not limited to menthol, mint oil, eucalyptus oil, carnation oil, ginger oil, lavender oil, sweet orange oil and their mixtures. Preferably it is menthol and the amount is from 0.01 to 2.0%, preferably from 0.05 to 1.0%, more preferably from 0.1 to 0.5% by weight of the total composition.

[0034] Suitable sweetening agents may comprise but not limited to sorbitol, saccharin, saccharin sodium, aspartame, fructose, isomalt, maltitol, maltose, mannitol, sucrose, xylitol, glycerin and their mixtures, and the amount is from 0.01 to 2.0%, preferably 0.1 to 1.0% by weight of the total composition. Preferably the sweetening agent is saccharin sodium.

[0035] Suitable dyes may comprise but not limited to Patent Blue, quinoline yellow, orange G and mixtures thereof. Preferred dye is patent blue E 131.

[0036] In one embodiment, the pharmaceutical composition according to the present invention comprises most preferably on a weight basis:

(i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof,
(ii) 0.10 to 10.0% dexpanthenol or salts thereof,
(iii) 0.01 to 2.0% menthol,
(iv) 0.1 to 5.0% sodium hydroxide,
(v) 5.0 to 20.0% sorbitol,
(vi) 0.01 to 2.0% saccharine sodium,
(vii) 5.0 to 25% glycerin,
(viii) 0.1 to 5.0% polyoxyl 40 hydrogenated castor oil,
(ix) 0.01 to 0.50% methyl paraben,
(x) 0.01 to 0.20% propyl paraben,
(xi) 5.0 to 15.0% ethyl alcohol,
(xii) 0.0001 to 0.001% patent blue

[0037] In another embodiment, this pharmaceutical composition may also comprise chlorhexidine or pharmaceutically acceptable salts thereof in addition to flurbiprofen or pharmaceutically acceptable salts thereof and dexpanthenol or pharmaceutically acceptable salts thereof which does not cause the staining of the teeth which is an unwanted effect of chlorhexidine in oral aqueous preparations.

[0038] In one embodiment, the topical aqueous pharmaceutical compositions of the invention comprise from 0.01 to 3.00% chlorhexidine or salts and esters thereof, preferably from 0.05 to 2.50%, more preferably from 0.10 to 2.0% by weight of the total composition.

[0039] According to this embodiment, the pharmaceutical composition according to the present invention comprises most preferably on a weight basis:

(i) 0.01 to 5.0% flurbiprofen or pharmaceutically acceptable salts thereof;
(ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof;
(iii) 0.01 to 3.0% chlorhexidine or pharmaceutically acceptable salts thereof;

[0040] According to the more preferred embodiment, the pharmaceutical composition according to the present invention comprises most preferably on a weight basis:

(i) 0.01 to 5.00% flurbiprofen or pharmaceutically acceptable salts thereof,
(ii) 0.10 to 10.0% dexpanthenol or pharmaceutically acceptable salts thereof,
(iii) 0.01 to 3.00% chlorhexidine or pharmaceutically acceptable salts thereof,
(iv) 0.01 to 2.00% menthol,
(v) 0.1 to 5.0% sodium hydroxide,
(vi) 5.0 to 20.0% sorbitol,
(vii) 0.01 to 2.0% saccharine sodium,
(viii) 5.0 to 25% glycerin,
(ix) 0.1 to 5.0% polyoxyl 40 hydrogenated castor oil,
(x) 5.0 to 15.0% ethyl alcohol,
(xi) 0.0001 to 0.001% patent blue

[0041] In one embodiment, the topical compositions of the invention may be in the form of mouthwash, mouth rinse and spray.

[0042] Accordingly, the said oral topical aqueous pharmaceutical compositions of the present invention may be used for treating oral mucosa and oral cavity inflammations, stomatitis, aphtha, periodontal diseases and non-specific epidermal and muco-epidermal infections and inflammation.

[0043] This invention is further defined by reference to the following examples. Although the examples are not intended to limit the scope of the present invention, they should be considered in the light of the description detailed above.

Example 1

0.25% Flurbiprofen and 5.0% Dexpanthenol Oral Topical Aqueous Solution/30 ml

[0044]

TABLE-US-00001 Ingredients Amount (mg/ml) Flurbiprofen 2.5 Dexpanthenol 50.0 Sorbitol 70 100.0 Saccharine sodium 1.5 Glycerin 150.0 Polyoxyl 40 hydrogenated castor oil 10.0 Methyl paraben 0.9 Propyl paraben 0.2 Ethyl alcohol 80.0 Patent blue E131 0.004 Menthol 1.6 Sodium hydroxide (pH = 6.7) 30.0-40.0 Purified water q.s q.s: Quantum Sufficiat (sufficient quantity)

[0045] Preparation of the Oral Topical Aqueous Solution:

[0046] Step 1: Flurbiprofen was dissolved in ethyl alcohol, methyl paraben and propyl paraben and stirred until it dissolves (apprx. 10 min.)

[0047] Step 2: Dexpanthenol is stirred in purified water until it dissolves (apprx. 10 min.)

[0048] Step 3: Step 1 and step 2 is mixed for 10 min.

[0049] Step 4: Adding sodium hydroxide to the solution in step 3 and stirred for 10 min.

[0050] Step 5: Polyoxyl 40 hydrogenated castor oil, glycerin and sorbitol 70 are added to the solution in step 4 and stirred for 15 min.

[0051] Step 6: Adding saccharine sodium to the solution in step 5 and stirred for 10 min. and then patent blue E131 is added and stirred further 5 more min.

[0052] Step 7: menthol is dissolved in ethyl alcohol and added to the solution in step 6 and stirred for 10 min.

[0053] Step 8: The pH of the solution was adjusted to 6.7 by adding sodium hydroxide to the solution and sufficient amount of purified water is added to the final solution to make the volume of the solution.

Example 2

0.25% Flurbiprofen, 5.0% Dexpanthenol and 0.12% Chlorhexidine Oral Topical Aqueous Solution/30 ml

[0054]

TABLE-US-00002 Ingredients Amount (mg/ml) Flurbiprofen 2.5 Dexpanthenol 50.0 Chlorhexidine gluconate 1.2 Sorbitol 70 100.0 Saccharine sodium 1.5 Glycerin 150.0 Polyoxyl 40 hydrogenated castor oil 10.0 Ethyl alcohol 80.0 Patent blue E131 0.004 Menthol 1.6 Sodium hydroxide (pH = 6.7) 30.0-40.0 Purified water q.s q.s: Quantum Sufficiat (sufficient quantity)

[0055] Preparation of the Oral Topical Aqueous Solution:

[0056] Step 1: Flurbiprofen was dissolved in ethyl alcohol and stirred until it dissolves (apprx. 10 min.)

[0057] Step 2: Adding sodium hydroxide to the solution of step 1 and stirred for 10 min.

[0058] Step 3: Polyoxyl 40 hydrogenated castor oil, glycerin, sorbitol 70 and purified water are added to the solution in step 2 and stirred for 15 min.

[0059] Step 4: Adding chlorhexidine gluconate with purified water to the solution in step 3 and stirred for 10 min. (Mixture 1)

[0060] Step 5: Dexpanthenol is dissolved in purified water in another container (Mixture 2)

[0061] Step 6: Mixture 1 and mixture 2 is mixed for 10 min.

[0062] Step 7: Adding saccharine sodium to the solution in step 6 and stirred for 10 min. and then patent blue E131 is added and stirred further 5 more min.

[0063] Step 8: Menthol is dissolved in ethyl alcohol and added to the solution in step 7 and stirred for 10 min.

[0064] Step 9: The pH of the solution was adjusted to 6.7 by adding sodium hydroxide to the solution and sufficient amount of purified water is added to the final solution to make the volume of the solution.