GB2392384A

GB2392384A - Compositions for topical application

Info

Publication number: GB2392384A
Application number: GB0219974A
Authority: GB
Inventors: Martin Whitefield; Andrew James Dixon
Original assignee: Diomed Developments Ltd
Current assignee: Diomed Developments Ltd
Priority date: 2002-08-28
Filing date: 2002-08-28
Publication date: 2004-03-03
Anticipated expiration: 2022-08-28
Also published as: GB2392384B; GB0219974D0

Abstract

The invention provides an anhydrous pharmaceutical composition in the form of a paste which is suitable for topical application to an oral mucosal surface comprising 50 to 85 wt% of a hydrophobic vehicle which is a mixture of a liquid paraffin and a white soft paraffin; 5 to 20 wt% of a non-neutralised carbomer; and 10 to 45 wt% of a water-soluble adhesive polymer; these percentages being based on the total weight of the composition, wherein the non-neutralised carbomer and the water-soluble adhesive polymer are in the form of non-swelled particles.

Description

1 2392384

- 1 COMPOSITIONS FOR TOPICAL APPLICATION

The present invention relates to a pharmaceutical composition for topical application to an oral mucosal 5 surface, and more particularly to compositions capable of adhering to the oral mucosal surface.

The surface of an oral mucous membrane is maintained in a moist condition by secretions from the underlying 10 glands. It is difficult to design a pharmaceutical vehicle or formulation for topical use on such mucous membranes which remains sufficiently adherent in use to exert its required function. It would be advantageous to provide a vehicle or formulation with 15 improved and/or prolonged adhesiveness, particularly in the treatment of diseases such as aphthous ulcers.

There are a number of topically applied medicated preparations available which are recommended for use 20 to treat this condition, but they all suffer from the same disadvantage, namely that their effects are transient because the vehicle used does not allow the preparation to remain on the site of treatment for more than a short period of time. This is due to one 25 or both of two factors: i) the adhesion of the formulation to the moist epithelium is not very satisfactory; and/or ii) the active ingredient of the formulation is quickly diluted and washed away by the 30 surrounding aqueous secretions.

Most of the preparations currently used for application to mucosal surfaces are based on conventional water and/or alcoholic based gels which 35 contain water-soluble polymers, e.g. cellulose derivatives, carbomer salts or gelatin.

Although these polymers do form gels capable of adhering to a moist surface, their effect is only transient as they soon start to dissolve in the aqueous secretions of the mucosal surface, especially 5 at physiological temperatures, i.e temperatures in the region of 37 C, and the preparation is quickly washed away from the site of application. Furthermore, the polymers in such preparations are already fully swollen, thereby enormously increasing the viscosity 10 of the formulation, even at low polymer concentrations. This severely limits the amount of the polymer which can be incorporated into the vehicle, which results in significantly reduced adhesiveness.

We believe that the power of adhesion is determined by 15 the concentration of the polymer in contact with the mucous membrane. This type of formulation therefore has very poor adhesiveness because the concentration of the polymer is necessarily limited by the viscosity of the formulation and the viscosity increases to 20 unmanageable levels if the concentration of polymer is raised above low levels.

There is, therefore, a need for a composition which is suitable for direct topical application to the oral 25 mucosal surface in order to treat aphthous ulcers and other forms of ulcerative stomatitis, which is convenient to use and which adheres to the oral mucosa surface more strongly and/or for a longer period than that provided by the presently available compositions, 30 thus allowing it to exert its required function.

It has been discovered that by incorporating a water-

insoluble hydrophilic adhesive polymer together with a water-soluble adhesive polymer into a hydrophobic 35 vehicle a composition is formed which meets this requirement.

- l The present invention accordingly provides an anhydrous pharmaceutical composition in the form of a paste which is suitable for topical application to an oral mucosal surface, comprising: 5 50 to 85 wt% of a hydrophobic vehicle; 5 to 20 wt% of a non-neutralised carbomer; and 10 to 45 wt% of a water-soluble adhesive polymer; the above percentages being based on the total weight of the composition, wherein the non-neutralised 10 carbomer and water-soluble adhesive polymer are in the form of non-swelled particles.

The pH of a human's mouth is normally approximately pH 7.4, i.e. above neutral. When the composition is 15 applied to a moist mucous membrane, there are a sufficient number of particles of suspended non-

neutralised carbomer on the surface of, and throughout, the vehicle to allow rapid absorption of water into the formulation, which, particularly at the 20 pH of 7 and above, causes it to swell, even though the vehicle itself is hydrophobic. The hydrophobic vehicle slows down the absorption of the water. Consequently, as soon as contact with moisture occurs, the composition immediately develops into a strongly 25 adhesive, highly viscous gel. The water soluble adhesive polymer hydrates more slowly than the carbomer. Its addition, therefore, provides a more robust and persistent protective film in the mouth which is retained longer as it is much more resistant 30 to mechanical attrition.

This composition is in the form of a paste so it is a suitable consistency for topical application to an oral mucosal surface. The definition of "paste" in the 35 context of the present invention defines an adhesive pharmaceutical composition of semi-solid consistency.

The viscosity of the pharmaceutical composition is

- 4 such to allow it to be sufficiently soft to issue from a container, for example a collapsible tube, and sufficiently stiff to remain within the area of application. The hydrophobic vehicle is anhydrous and has virtually no polar characteristics or water miscibility.

Furthermore, the non-neutralised carbomer and the water-soluble adhesive polymer are in the form of non 10 swelled particles. Accordingly, these considerations exclude the use of alcohols, e.g., ethanol, glycerol or propylene glycol. This is due to the fact that with such vehicles there is a sharp increase in viscosity due to swelling, even at low concentrations 15 of the polymers, caused by hydrogen bonding or moisture absorption, and this precludes their use as effective vehicles in the composition of the present invention. 20 The hydrophobic vehicle provides a dispersing medium of suitable viscosity for the polymer. Suitable hydrophobic vehicles are paraffins, such as a liquid paraffin and a white soft paraffin, isopropyl myristate, and hydrophobic polymeric silicones such as 25 dimethicones. The hydrophobic vehicle can be used singly or in a combination of two or more.

In a preferred embodiment the hydrophobic vehicle is a mixture of a liquid paraffin and a white soft 30 paraffin. The weight ratio of liquid paraffin to white soft paraffin is desirably from 1:0.5 to 1:2, preferably 1:0.75 to 1:1.5, and most preferably approximately 1:1.

35 A "liquid paraffin" in the context of the present invention is a purified mixture of liquid saturated hydrocarbons obtained from petroleum.

l - 5 A "white soft paraffin" in the context of the present invention is a semi-solid mixture of hydrocarbons obtained from petroleum and bleached.

5 Examples of liquid paraffins and white soft paraffins which can be used are liquid paraffin EP (European Pharmacopoeia) and white soft paraffin BP (British Pharmacopoeia). 10 The hydrophobic vehicle is included in the composition in an amount of from 50 to 85 wt%, preferably from 55 to 70 wt% and most preferably approximately 60 wt%.

The non-neutralised carbomer i.e. a copolymer based on 15 acrylic acid in the free acid form, is a water-

insoluble hydrophilic adhesive polymer. It is substantially insoluble in water and insoluble in the vehicle at physiological temperatures. The carbomer is suspended in the vehicle in the water-insoluble free 20 acid form and is in the form of non-swelled particles.

Any grade of carbomer which is suitable for use in the mouth can be used. In a preferred embodiment a high viscosity grade carbomer is preferably used such as 25 that sold under the trade name Carbopol 974P (Pharmaceutical grade, manufactured by B.F. Goodrich) and that sold under the trade name Carbopol 980 (Pharmaceutical Grade, manufactured by B.F. Goodrich).

In a preferred embodiment Carbopol 974P is used which 30 is the grade recommended by the manufacturer for oral dosage forms.

The non-neutralised carbomer is included in the composition in an amount of from 5 to 20 wt%, 35 preferably from 7 to 15 wt% and most preferably approximately 10 wt%. The non-neutralised carbomer can be used singly or in a combination of two or more.

l - 6 - The water-soluble adhesive polymer used in the composition of the present invention can be any polymer which is insoluble in the vehicle and which can be used safely in the mouth. The water-soluble 5 adhesive polymer is present in the composition in the form of non-swelled particles.

In a preferred embodiment the water-soluble adhesive polymer is a watersoluble cellulose derivative such 10 as an alkyl or hydroxyalkyl(substituted) cellulose.

Suitable examples include hydroxypropylcellulose, methylhydroxyethylcellulose or methylhydroxypropylcellulose. Hydoxypropylcellulose is preferred. The water-soluble 15 adhesive polymer can be used singly or in a combination of two or more.

Various grades of water-soluble adhesive polymers are available. All grades are suitable for use in the 20 compositions. High viscosity grade water-soluble adhesive polymers are preferred such as hydroxypropylcellulose which is sold under the trade name Klucel HXF (high viscosity food grade, conforming to EP specification and manufactured by Aqualon).

The water-soluble adhesive polymer is included in the composition in an amount of from 10 to 45 wt%, preferably from 20 to 35 wt%, and more preferably approximately 30 wt%.

The compositions according to the invention can optionally comprise one or more further components such as an anaesthetic, antiseptic, topical corticosteroid, non-steroidal anti-inflammatory agent, 35 antifungal agent, colouring agent or flavouring agent.

However, the compositions may consist essentially or consist only of a hydrophobic vehicle, a non

7 - neutralised carbomer and a water-insoluble hydrophilic adhesive polymer, optionally together with an anaesthetic, antiseptic, topical corticosteroid, non-

steroidal anti-inflammatory agent, antifungal agent, 5 colouring agent and/or flavouring agent.

It is preferable to incorporate into the composition of the present invention a topical anaesthetic to relieve the pain. Any anaesthetic suitable for use in 10 the mouth can be used. Suitable anaesthetics include amide based and ester based anaesthetics.

Amide based anaesthetics are preferred. Examples of suitable amide based anaesthetics include lignocaine 15 hydrochloride and prilocaine hydrochloride. Examples of suitable ester based anaesthetics include amethocaine hydrochloride and benzocaine hydrochloride. The anaesthetic can be used singly or in a combination of two or more. In a preferred 20 embodiment the anaesthetic used is lignocaine hydrochloride. The anaesthetic can, for example, be included in the composition in an amount of from 0.1 to 4 wt%, 25 preferably from 0.4 to 1.2 wt% and most preferably approximately 0.66 wt%.

It is further preferable to incorporate into the vehicle a topical antiseptic which can, for example, 30 remove any infection present.

Examples of suitable antiseptics include aminacrine hydrochloride, acriflavine hydrochloride, proflavine hemisulphate or triclosan. The antiseptic can be used 35 singly or in a combination of two or more. Typically the antiseptic used is aminacrine hydrochloride.

f The antiseptic can, for example, be included in the composition in an amount of from 0.025 to 0.2 wt%, preferably from 0.04 to 0.1 wt% and most preferably approximately 0.050 wt%.

A topical corticosteroid can also be incorporated into the composition of the present invention. Examples of suitable topical corticosteroid agents include hydrocortisone, betamethasone valerate, triamcinolone 10 acetonide and flucinolone acetonide. The corticosteroid agents can be used singly or in a combination of two or more. The corticosteroid can, for example, be included in an amount of from 0.02 wt% to 1.5 wt%. For example, hydrocortisone can be 15 present in an amount of approximately 1 wt%, betamethasone valerate in an amount of approximately 0.1 wt%, triamcinolone acetonide in an amount of approximately 0.1 wt% and flucinolone acetonide in an amount of approximately 0.025 wt%.

A topically active non-steroidal anti-inflammatory agent can also be incorporated into the composition of the present invention. Examples of suitable topically active non-steroidal anti-inflammatory agents include 25 ibuprofen and ketoprofen. The non-steroidal anti-

inflammatory agent can be used singly or in a combination of two or more. The anti-inflammatory agent can, for example, be included in the composition in an amount of from 1 wt% to 7 wt%, preferably from 2 30 wt% to 6 wt%. For example ibuprofen can be present in an amount of approximately 5 wt% and ketoprofen in an amount of approximately 2.5 wt%.

A topically active antifungal agent can also be 35 incorporated into the composition of the present invention. Examples of suitable topically active antifungal agents include ketoconazole and miconazole

9 - nitrate. The antifungal agent can, for example, be included in the composition in an amount of from 0.5 wt% to 3 wt%, preferably from 1.5 wt% to 2.5 wt%, and most preferably approximately 2 wt%.

Any flavouring agent which is suitable for use in the mouth may also be included in the composition.

Preferred agents are oil based flavouring agents such as peppermint oil. The flavouring agent can be, for 10 example, included in the composition in an amount of from 0.05 wt% to 1.5 wt%, preferably from 0.1 to 0.6 wt% and most preferably approximately 0.2 wt%.

In a preferred embodiment lignocaine hydrochloride is 15 present in an amount of approximately 0.660 wt% together with aminacrine hydrochloride in an amount of approximately 0.050 wt%.

A preferred composition of the present invention is an 20 anhydrous pharmaceutical composition suitable for topical application to an oral mucosal surface comprising approximately: 29.545 wt% liquid paraffin; 29. 545 wt% white soft paraffin; 25 10 wt% non-neutralised carbomer; 30 wt% hydroxypropylcellulose; 0.660 wt% lignocaine hydrochloride; 0.050 we% aminacrine hydrochloride; and 0.2 wt% peppermint oil.

The compositions can be prepared by mixing together, in any order, the required components.

The compositions can be used in a method of treatment 35 of the human or animal body by therapy. A suitable method of treatment is to apply to the affected area of the mucosal surface of a subject in need of such

treatment, an effective amount of the composition of the invention.

The compositions are suitable for application to the 5 mucosal surface. They can be used topically in the treatment of aphthous ulcers and other forms of ulcerative stomatitis.

The present invention also provides the use of the 10 compositions in the manufacture of a medicament for the treatment of aphthous ulcers or other forms of ulcerative stomatitis.

The compositions may be applied topically, for example 15 using a finger, to the affected area of the mucosal surface and immediately surrounding area of the mucosal surface with an amount sufficient to coat the areas with a film. In a preferred embodiment this amount is from 0.1 to 0.5 ml per application.

Desirably the composition should be applied to the affected area four times daily, preferably morning, afternoon, evening and night, over a period of about two weeks. It is evident, however, that the dosage 25 schedule may be altered depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compositions of the instant invention.

30 The compositions may be conveniently packed into small collapsible polyethylene tubes with a shaped narrow nozzle for ease of application and localization. An example is a 19 x 75 mm high density polyethylene tube with a low density polyethylene inclined nozzle and a 35 polypropylene cap, such as manufactured by Adelphi.

Alternatively, a collapsible aluminium tube (internally lacquered) with an applicator nozzle may

be used. It is important that the tubes minimise moisture and air entering.

The following Example further illustrates the present 5 invention.

EXAMPLE

A composition for the treatment of aphthous ulcers was made comprising, in percent by weight based on the 10 total weight of the composition: Liquid Paraffin EP 29.545% White Soft Paraffin BP 29.545% Carbomer (Carbopol 974P) 10.000% 15 Hydroxypropylcellulose (Klucel HXF) 30.000% Lignocaine hydrochloride 0.660% Aminacrine hydrochloride 0.050% Peppermint Oil 0.200% 20 Method of Manufacture 1. Mix the liquid paraffin and white soft paraffin with slight warming until homogeneous.

25 2. Add the lignocaine hydrochloride and the aminacrine hydrochloride and mix until dispersed.

3. Add the peppermint oil and mix until dispersed.

30 4. Add the carbomer and the hydroxypropylcellulose slowly with continuous mixing until fully dispersed to produce an homogenous product.

5. Pack into small polythene tubes with a shaped 35 narrow nozzle for ease of application and localization.

The local anaesthetic and antiseptic action provides fast relief of the discomfort associated with common mouth ulcers. The advantage of the composition is that the relief from each application lasts very much 5 longer than alternative commercially available preparations. This is due to the significantly increased adhesiveness of the composition and therefore its much greater retention at the affected site. Alternative preparations need to be applied as 10 frequently as even every 20 minutes whereas with this preparation, it may be sufficient to make an application only 3 to 4 times daily.

Claims

l l CLAIMS

1. An anhydrous pharmaceutical composition in the form of a paste which is suitable for topical 5 application to an oral mucosal surface comprising: 50 to 85 wt% of a hydrophobic vehicle; 5 to 20 wt% of a non- neutralised carbomer; and 10 to 45 wt% of a water-soluble adhesive polymer; the above percentages being based on the total weight 10 of the composition, wherein the non-neutralised carbomer and the water-soluble adhesive polymer are in the form of non-swelled particles.

2. A composition according to claim 1 wherein the 15 hydrophobic vehicle is paraffin.

3. A composition according to claim 2 wherein the hydrophobic vehicle is a mixture of a liquid paraffin and a white soft paraffin.

4. A composition according to claim 3 wherein the weight ratio of liquid paraffin to white soft paraffin is 1:1.

25

5. A composition according to any one of the preceding claims wherein the hydrophobic vehicle is present in an amount of from 55 to 70 wt%.

6. A composition according to any one of the 30 preceding claims wherein the non-neutralised carbomer is Carbopol 947P.

7. A composition according to any one of the preceding claims wherein the non-neutralised carbomer 35 is present in an amount of from 7 to 15 wt%.

8. A composition according to any one of the

preceding claims wherein the water-soluble adhesive polymer is a cellulose derivative.

9. A composition according to claim 8 wherein the 5 water-soluble adhesive polymer is hydroxypropylcellulose.

10. A composition according to any one of the preceding claims wherein the water-soluble adhesive 10 polymer is present in an amount of from 15 to 30 wt%.

11. A composition according to any one of the preceding claims wherein the composition further comprises on anaesthetic.

12. A composition according to claim 11 wherein the anaesthetic is present in an amount of from 0.1 to 5 wt% based on the total weight of the composition.

20

13. A composition according to claim 11 or 12 wherein the anaesthetic is lignocaine hydrochloride, prilocaine hydrochloride, amethocaine hydrochloride or benzocaine hydrochloride.

25

14. A composition according to any one of the preceding claims wherein the composition further comprises an antiseptic.

15. A composition according to claim 14 wherein the 30 antiseptic is present in an amount of from 0.025 to 0.5 wt% based on the total weight of the composition.

16. A composition according to claim 14 or 15 wherein the antiseptic is aminacrine hydrochloride, 35 acriflavine hydrochloride, proflavine hemisulfate or triclosan.

- 15

17. A composition according to any one of the preceding claims wherein the composition further comprises a flavouring agent.

5

18. An anhydrous pharmaceutical composition suitable for topical application to an oral mucosal surface comprising approximately: 29.545 wt% liquid paraffin; 29.545 wt% white soft paraffin; 10 10 % carbomer; 30 % hydroxypropylcellulose; 0.660 wt% lignocaine hydrochloride; 0.050 wt% aminacrine hydrochloride; and 0.2 wt% peppermint oil.

19. A composition according to any one of the preceding claims wherein the composition is in a collapsible tube.

20 20. A composition as defined in any one of the preceding claims for use in a method of treatment of the human or animal body by therapy.

21. A composition as defined in any one of claims 1 25 to 19 for use in a method of treatment of aphthous ulcers or another form of ulcerative stomatitis.

22. Use of a composition as defined in any one of claims 1 to 19 in the manufacture of a medicament for 30 the treatment of aphthous ulcers or another form of ulcerative stomatitis.

Amendments to the claims have been filed as follows _ CLAIMS

1. An anhydrous pharmaceutical composition in the form of a paste which is suitable for topical 5 application to an oral mucosal surface comprising: 50 to 85 wt% of a hydrophobic vehicle which is a mixture of a liquid paraffin and a white soft paraffin; 5 to 20 wt% of a non- neutralised carbomer; and 10 10 to 45 wt! of a water-soluble adhesive polymer) the above percentages being based on the total weight of the composition, wherein the non-neutralised carbomer and the water-soluble adhesive polymer are in the form of non-swelled particles.

2. A composition according to claim 1 wherein the weight ratio of liquid paraffin to white soft paraffin is 1:1.

20 3. A composition according to claim 1 or claim 2 wherein the hydrophobic vehicle is present in an amount of from 55 to 70 wt%.

4. A composition according to any one of the 25 preceding claims wherein the non-neutralised carbomer is Carbopol 947P.

5. A composition according to any one of the preceding claims wherein the non-neutralised carbomer 30 is present in an amount of from 7 to 15 wt%.

6. A composition according to any one of the preceding claims wherein the water-soluble adhesive polymer is a water-soluble cellulose derivative.

7. A composition according to claim 6 wherein the water-soluble adhesive polymer is

al id hydroxypropylcellulose. 8. A composition according to any one of the preceding claims wherein the water-soluble adhesive 5 polymer is present in an amount of from 15 to 30 wt%.

9. A composition according to any one of the preceding claims wherein the composition further comprises on anaesthetic.

10. A composition according to claim 9 wherein the anaesthetic is present in an amount of from 0.1 to 5 wit based on the total weight of the composition.

15 11. A composition according to claim 9 or 10 wherein the anaesthetic is lignocaine hydrochloride, prilocaine hydrochloride, amethocaine hydrochloride or benzocaine hydrochloride.

20. Use of a composition as defined in any one of claims 1 to 17 in the manufacture of a medicament for 25 the treatment of aphthous ulcers or another form of ulcerative stomatitis.

20 12. A composition according to any one of the preceding claims wherein the composition further comprises an antiseptic.

13. A composition according to claim 12 wherein the 25 antiseptic is present in an amount of from 0.025 to 0.5 wt% based on the total weight of the composition.

14. A composition according to claim 12 or 13 wherein the antiseptic is aminacrine hydrochloride, 30 acriflavine hydrochloride, proflavine hemisulfate or triclosan. 15. A composition according to any one of the preceding claims wherein the composition further 35 comprises a flavouring agent.

16. An anLydrous pharmaceutical composition suitable

- 1 for topical application to an oral mucosal surface comprising approximately: 29.545 wt% liquid paraffin; 29.545 wt% white soft paraffin) 5 10 % non-neutralised carbomer; 30 % hydroxypropylcellulose; 0.660 wt% lignocaine hydrochloride; 0.050 wt% aminacrine hydrochloride; and 0.2 wt% peppermint oil.

17. A composition according to any one of the preceding claims wherein the composition is in a collapsible tube.

15 18. A composition as defined in any one of the preceding claims for use in a method of treatment of the human or animal body by therapy.

19. A composition as defined in any one of claims 1 20 to 17 for use in a method of treatment of aphthous ulcers or another form of ulcerative stomatitis.