GB2236250A

GB2236250A - Ibuprofen solutions and topical compositions

Info

Publication number: GB2236250A
Application number: GB8921711A
Authority: GB
Inventors: John Francis Smith; Donald Peter Vaughan; Kenneth Murray Henderson
Original assignee: Mentholatum Co Ltd
Current assignee: Mentholatum Co Ltd
Priority date: 1989-09-26
Filing date: 1989-09-26
Publication date: 1991-04-03
Also published as: GB8921711D0

Abstract

Ibuprofen dissolves in benzyl alcohol to form a solution which can be admixed with a vehicle to form a stable topical composition. The solution can also comprise a pharmacologically acceptable alcohol, especially propylene glycol. The solubility of ibuprofen in propylene glycol is substantially enhanced when in the form of a solution in benzyl alcohol.

Description

(Case 2) IBUPROFEN SOLUTIONS AND TCPICAL COt1POSITIONS CONTAINING SAME The present invention relates to topical ibuprofen formulations.

Ibuprofen (ie. (isobutylphenyl)propionic acid) is a white crystalline drug, insoluble in water but relatively soluble in organic solvents'such as alcohol (1 in 1.5); chloroform (1 in l'); ether (1 in 2) and acetone (1 in 1.5).

Ibuprofen usually is taken orally and, although a number of topical formulations have been proposed, we are not aware of any satisfactory topical formulations.

However, it often would be preferred to administer ibuprofen by topical application to an affected area so as to permit absorption through the skin. For example, in the treatment of rheumatic pain and/or inflammation, it is desirable to sustain a high local concentration of ibuprofen in the affected area of the body. Whereas oral administration to provide such local concentration would result in unacceptably high concentrations of ibuprofen throughout the body, topical application allows ibuprofen to accumulate only where it is needed.

In this connection, it is believed that solution dosage forms offer the best prospects of efficient percutaneous absorption of ibuprofen from topical formulations. Such forms provide the best possible particle size distribution (Smith J.F. (1969) J. Hosp.

Pharm.) and solutions which release a drug as an active principle ensure enhanced absorption (Dempski et al (1969) J. Pharm. Sci. 58). Further, a saturated solution has the highest thermodynamic activity of â drug and optimizes release and penetration. (Ostrenga et al (1971) J. Invest. Derm.).

Until June 1989, there were no topical formulations of ibuprofen available in the UK but such formulations were previously available in some countries. However, these formulations are rather unstable, and liable to crystallising out ibuprofen with time. Such crystallisation is inconvenient and may be uncomfortable to the patient. Furthermore, it reduces the effective concentration of ibuprofen since crystallised ibuprofen plays little role in the percutaneous transport/absorption process.

The present Applicants have experimented with topical formulations using conventional vehicles containing long chain cetyl and stearyl alcohols. They found that ibuprofen appears to react with these alcohols, thus reducing the concentration of the active ingredient for absorption. There was also a marked tendency for the ibuprofen to crystallise on storage as described above.

Mineral and vegetable oils dissolve ibuprofen but, even at very high oil concentrations, the ibuprofen soon crystallises out. Oleic acid also dissolves ibuprofen but the solution has an unpleasant smell and is sticky and liable to autoxidation.

Vehicles based on combinations of oleic acid and medium chain length oils were investigated with various emulsifying agents - but avoiding cetyl and stearyl alcohols. These combinations prevented ibuprofen from crystallising out of an organic solution, but the emulsion formed could not be stiffened or settled sufficiently to withstand storage at 35 to 37"C for several months. Further, the H.L.B. (ie. hydrophiliclipophilic balance) was higher than considered desirable for topical use.

Benzyl alcohol has been used in pharmacy for decades as an antimicrobial preservative, local anaesthetic and antipuritic in topical formulation.

However, we are not aware of any disclosure of the use of benzyl alcohol as a solvent for a propionic acid derivative or of any other disclosure which would have led those skilled in the art of topical formulations to consider the use of benzyl alcohol to overcome the problem of topically formulating ibuprofen.

It has now surprisingly been found that ibuprofen forms a stable solution in benzyl alcohol and that the use of such a solution in a topical pharmaceutical composition leads to greatly improved stability, and a significant reduction in the tendency for ibuprofen to crystallise. It is also believed that the solution enhances penetration of ibuprofen through the skin.

A further advantage of the use of benzyl alcohol is that it enhances the solubility of ibuprofen in other alcohols, especially glycols such as propylene glycol and Macrogols (ie. polyethylene glycols). In particular, the solubility of ibuprofen in glycols when added as a solution with benzyl alcohol is at least twice that when added in crystalline form. Thus, by including benzyl alcohol in a topical formulation containing ibuprofen and a glycol, it is possible to reduce the concentration of the glycol. This higher concentration of ibuprofen relative to glycol is believed to facilitate absorption of ibuprofen through the skin.

Accordingly the present invention provides a solution of ibuprofen in a solvent comprising benzyl alcohol. The invention further provides a topical pharmaceutical composition comprising said solution in a pharmaco ogically acceptable vehicle and the use of benzyl alcohol to stabilize a topical composition comprising ibuprofen against crystallisation of ibuprofen therefrom.

Usually the solution of the invention will be formed by mixing the ibuprofen, benzyl alcohol and any other components thereof at ambient temperature.

However, the solution could be formed by heating the components together whilst mixing or by stirring or otherwise mixing a fused mass of the components and then cooling the hot mixture.

Any relative proportions of ibuprofen and benzyl alcohol which provide a solution which is liquid at ambient temperature can be used. Suitably, the amount of ibuprofen will be 1 to 45 percent by weight based upon the weight of the solution.. However, the amount of ibuprofen preferably is 40 to 45 percent by weight of the solution.

As mentioned previously, the solubility of ibuprofen in alcohols, especially glycols, is enhanced by the presence of benzyl alcohol. Accordingly, it is preferred to include a pharmaceutically acceptable alcohol in the solvent of the invention when it is to be used to formulate a topical gel. When the solvent contains a glycol, it usually will be present in an amount by weight of up to 200 percent by weight based upon the weight of benzyl alcohol. Preferably said amount is 50 to 150 percent by weight and especially 100 percent by weight.

The solution of the invention can be admixed with any compatible pharmacologically acceptable vehicle to form a topical composition. Preferably, the vehicle is an aqueous gel, cream or lotion. Carbomer (ie.

carboxypolymethylene; carboxyvinyl polymer) is particularly suitable as a gelling agent in said aqueous gel vehicle.

Usually the concentration of ibuprofen in the topical compositions of the invention will be in the range 0.1 to 20 percent by weight but any pharmacologically active concentration can be used.

Preferably, the ibuprofen concentration will be 2 to 12 percent by weight and especially 4 to 6 percent by weight. Said amounts are by weight based upon the total weight of the topical composition.

The topical compositions of the invention can contain other compatible pharmacologically acceptable additives conventionally used in topical formulations such as antimicrobial agents, colorants, perfumes and pH modifiers, antioxidants, and stabilizers. Further, they can contain other compatible pharmacologically active substances such as other non-steroidal anti-inflammatory agents, steroids, antibiotics and antibacterials.

The present invention is illustrated by the following non-limiting examples.

EXAMPLE 1 4 g Crystalline ibuprofen was mixed with 5 g benzyl alcohol to form an oil phase. This oil phase, was then mixed with Carbomer (Carbopol 941), ethanol and water to form a topical gel having the following composition: Ibuprofen 4 g Benzyl alcohol 5 g Carbomer* 1-2 g Ethanol qs water to 100 g * Carbopol 941 EXAMPLE 2 4 g Crystalline ibuprofen was mixed with 5 g benzyl alcohol and 5 g propylene glycol to form an oil phase, which was then mixed with Carbomer, ethanol and water to form a topical gel having the following composition: Ibuprofen 4 g Benzyl alcohol 5 g Propylene glycol 5 g Carbomer* 1-2 g Ethanol qs Water to 100 g * Carbopol 941 The gels of Examples 1 and 2 were found to be completely stable after storage for 6 months at ambient temperature. At the end of the period of storage there was no significant loss of dissolved ibuprofen through crystallisation.

Claims

CLAIMS:

1. A solution of ibuprofen in a solvent comprising benzyl alcohol.

2. A solution as claimed in Claim 1, wherein the solvent consists essentially of benzyl alcohol.

3. A solution as claimed in Claim 1 or Claim 2, wherein the ibuprofen is present in an amount in the range 1 to 45 percent by weight of the solution.

4. A solution as claimed in Claim 3, wherein the amount by weight of ibuprofen is 40 to 45 percent by weight of the solution.

5. A solution as claimed in any one of Claims 1, 3 and 4, wherein the solvent comprises also another pharmacologically acceptable alcohol.

6. A solution as claimed in Claim 5, wherein said alcohol is a glycol.

7. A solution as claimed in Claim 6, wherein glycol is propylene glycol.

8. A solution as claimed in Claim 7, wherein the solvent consists essentially of benzyl alcohol and propylene glycol.

9. A solution as claimed in any one of Claims 6 to 8, wherein the glycol is present in an amount of 50 to 150 percent by weight of benzyl alcohol.

10. A solution as claimed in Claim 9, wherein the amount by weight of propylene glycol is equal to the amount by weight of benzyl alcohol.

11. A topical pharmaceutical composition comprising a solution as claimed in any one of the preceding claims in a pharmacologically acceptable vehicle.

12. A topical composition as claimed in Claim 11, wherein the vehicle is an aqueous gel.

13. A topical composition as claimed in Claim 11 or Claim 12, wherein the ibuprofen content is 2 to 12 percent by weight of the composition.

14. A topical composition as claimed in Claim 13, wherein said ibuprofen content is 4 to 6 percent by weight of the composition.

15. The use of benzyl alcohol to stabilize a topical composition comprising ibuprofen against crystallisation of ibuprofen therefrom.

16. A solution as claimed in Claim 1 and substantially as hereinbefore described in either of the Examples.

17. A topical pharmaceutical composition as claimed in Claim 11 and substantially as hereinbefore described in either of the Examples.