WO2011070318A2 - Topical formulation - Google Patents

Topical formulation Download PDF

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Publication number
WO2011070318A2
WO2011070318A2 PCT/GB2010/002240 GB2010002240W WO2011070318A2 WO 2011070318 A2 WO2011070318 A2 WO 2011070318A2 GB 2010002240 W GB2010002240 W GB 2010002240W WO 2011070318 A2 WO2011070318 A2 WO 2011070318A2
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WO
WIPO (PCT)
Prior art keywords
topical formulation
ibuprofen
propylene glycol
water
alcohol
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PCT/GB2010/002240
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French (fr)
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WO2011070318A3 (en
Inventor
Andrew Kirkwood
Adrian Davis
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Reckitt Benckiser Healthcare International Limited
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Publication of WO2011070318A2 publication Critical patent/WO2011070318A2/en
Publication of WO2011070318A3 publication Critical patent/WO2011070318A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a topical pharmaceutical composition having improved skin penetration properties but with aesthetics that meet consumer and patient expectations and ensure compliance.
  • the present invention relates to such a topical pharmaceutical aqueous gel having improved skin penetration properties which comprises an NSAID.
  • Transdermal delivery for local or regional effect of pharmaceutically active compounds, was developed to address the problems associated with orally taken drug formulations, e.g. actives breaking down in the organs in the body such as the liver and without the necessity for the whole body to be treated.
  • transdermal technology was driven by the development of patches.
  • the technology maintained the drug at saturation levels and included a moderately polar solvent, but with a lipid enhancer, often a fatty acid, alcohol or ester derivative.
  • a moderately polar solvent also increased the lipid enhancer solubility in the stratum corneum barrier, and the lipid enhancer also increased the polar solvent diffusivity, synergy was often found with this "co-enhancer" technology.
  • Propylene glycol is an excellent solvent for many drugs and, as discussed, has been widely used to enhance the skin penetration of range of drugs, including antivirals, corticosteroids, testosterone, antihistamines, cardiovasculars and nonsteroidals including ibuprofen.
  • propylene glycol especially at the high concentration required to demonstrate an enhancer effect, is extremely hydroscopic and thus tacky to the touch which limits consumer and patient acceptance and compliance.
  • propylene glycol may be replaced by enhancers such as Transcutol or dimethyl isosorbide, these are not as effective and also suffer from poor aesthetics.
  • Propylene glycol is immiscible with many fatty acid derivatives, for example isopropyl myristate, such that the mixture is a two-phase system.
  • WO 02/1 1768 discloses compositions which comprise a fatty alcohol and a diethylene glycol monoalcohol ether.
  • the compositions further include Carbomer as a gelling agent.
  • the lipid enhancers used in combination with propylene glycol include straight chain saturated fatty acid, broadly from C 8 -C 16 and commonly selecting from the fatty acid, fatty alcohol of fatty ester derivatives. Because propylene glycol penetrates into and through the stratum corneum barrier of the skin much faster than fatty acid derivatives, much higher doses of propylene glycol are required, and for optimum effect the fatty acid should be present at around 5% of the dose of propylene glycol.
  • C 12 -C 14 fatty acids isopropyl esters are only miscible at 1-2% of propylene glycol and are not optimised.
  • C12 fatty acid alcohol is very miscible with propylene glycol and when present at around 5% of the dose of propylene glycol would itself be at a low degree of saturation which would limit its skin penetration enhancement potential.
  • the C 12 -C 14 fatty acids have a further benefit in that they are relatively more soluble in propylene glycol-water, than, for example, the corresponding esters and alcohols.
  • Water-propylene glycol bases are much more acceptable from a cosmetic perspective than propylene glycol alone, but would be expected to have reduced skin penetration due to the reduced propylene glycol concentrations. Niall, this statement is probably true, especially at the pH of Bronson, but I don't know for sure. Of course, as we state, the alcohol is more soluble in propylene glycol. I would leave this in. It is a nice idea and adds to the story.
  • Ibuprofen is a potent NSAID with moderately good skin penetration.
  • the onset, intensity and duration of local analgesic and antiinflammatory activity may be improved by use of skin penetration enhancers, including propylene glycol.
  • skin penetration enhancers including propylene glycol.
  • ibuprofen is a low melting point drug, melting at around 70 degrees centrigrade, and consequently has relatively high solubility in most solvent.
  • Herkenne et al. have shown that the saturated solubility of ibuprofen in propylene glycol is in excess of 40% w/v whereas that in water is only approximately 0.014% w/v.
  • the use of propylene glycol alone, or in the presense of a low concentration of a fatty acid dervative, such as a C 12 -C 14 fatty acid has the disadvantage that at 5% of ibuprofen (the amount normally contained in topical products) the drug is at a low level of saturation (of approximately l/8 th saturation) which serves to reduce the overall skin penetration of ibuprofen from propylene glycol alone-fatty acid systems, such as propylene glycol C 12 or C 14 fatty acid.
  • a topical formulation comprising:
  • a gelling agent selected from the group consisting of non-ionic polymers
  • the formulation can be in the form of a gel.
  • the NSAID can be selected from the group consisting of ibuprofen, ketoprofen, flurbiprofen, diclofenac, naproxen.
  • the NSAID can be selected from ibuprofen, ketoprofen or naproxen.
  • the polyhydric alcohol is selected from the group consisting of monomeric polyhydric alcohols such as a C 2 - C 6 glycol, or polymeric polyhydric alcohols such polyethylene glycol, polypropylene glycol or mixtures thereof.
  • the polyhydric alcohol can be propylene glycol or butylene glycol.
  • the fatty acid is preferably lauric acid, or myristic acid.
  • a preferred C 2 - C 4 alcohol is isopropyl alcohol.
  • the ratio of water: C 2 - C 4 alcohol is from 90%: 10% to 50%:50%.
  • the ratio of fatty acid to polyhydric alcohol is from 1%:99% to 15%:85%.
  • a preferred ratio is 5%:95% to 10%:90%.
  • the gelling agent can be selected from hydroxyethyl cellulose, hydroxyeihylmethyl cellulose, hydroxymethylpropyl cellulose, hydroxypropyl cellulose, and polyacrylamide-based gelling agents such as those marketed under the Carbopol brand name.
  • Preferred gelling agents are hydroxypropyl cellulose or hydroxyethyl cellulose.
  • the optional pharmaceutical excipients include one or more diluents, one or more colourings, pH controlling agents, fillers, flow aids, preservatives, antioxidants, moisture scavengers, colourants and processing aids.
  • a preferred excipient is a pH controlling agent such as an acid or a base.
  • a base such as sodium hydroxide or potassium hydroxide is a preferred pH controlling agent, although any pharmaceutically acceptable base may be used.
  • the compositions can include an additional analgesic agent. Typically, the compositions do not contain pharmaceutically active compounds other than analgesics.
  • the gel can comprise
  • Sensorially active ingredients that stimulate the cold and warm receptors in the skin and artificially produce a cool or warming feeling may also be considered for inclusion.
  • Example of such materials include Menthol and Capsaicin which target cooling and warming receptor respectively and can be used to improve formulation organoleptics.
  • the gel can further comprise up to 10% menthol.
  • the gel can comprise
  • composition consists essentially of components (a) to (h).
  • gel comprises
  • the gel comprises
  • Figure 1 illustrates the miscibility of FAD in 100% propylene glycol against FAD type and carbon chain length.
  • Figure 2 illustrates the amount of ibuprofen in ⁇ g/cm 2 penetrated with time from Ibugel and two experimental formulations one containing hydroxylethyl cellulose (HHX) and one containing hydroxypropyl cellulose (HF); and
  • Figure 3 illustrates the percentage of dose of applied ibuprofen penetrated with time from Ibugel and two experimental formulations one containing hydroxylethyl cellulose (HHX) and one containing hydroxypropyl cellulose (HF).
  • HHX hydroxylethyl cellulose
  • HF hydroxypropyl cellulose
  • the formulations can be made in the following way.
  • propylene glycol (42.3 lg) was added to lauric acid(4.19g) and the resulting mixture was heated (to 60-70°C) while mixing for at least 5 minutes or until a clear solution is formed.
  • Ibuprofen (5.00g) was added with stirring for 5 minutes.
  • an aqueous solution of sodium hydroxide (0.50g) in deionised water (31.55g) was prepared. The aqueous sodium hydroxide solution was added to the propylene glycol/lauric acid mixture, and stirring was continued for a minimum of 5 minutes.
  • a solution of isopropyl alcohol (13.95g) and the hydroxyethyl cellulose (1.50g) was prepared, and to this solution was added menthol with further stirring for a minimum of 10 minutes or until the menthol is dissolved.
  • the resulting isopropyl alcohol/hydroxyethyl cellulose/menthol mixture was added to the solution of aqueous sodium hydroxide, propylene glycol and lauric acid. The combined mixture was gently stirred for a a minimum of 2 hours until a homogeneous mixture was formed.
  • Example formulations Nos 1 & 2 of non-aqueous and an aqueous alcoholic gel are given below in Tables 1 & 2 respectively:
  • the ratio of lauric acid-PG to IPA was chosen as 70:30.
  • Hydroxypropyl cellulose was chosen as a gelling agent for this solvent- rich gel.
  • Table 2 there is shown an aqueous alcoholic (IPA) gel (example 2) based on Ci 2 acid (lauric acid)-PG residual phase.
  • IPA aqueous alcoholic
  • Table 3 (examples 3 & 4) shows the actual batch weights and theoretical weights (in brackets) for 20 g nominal batches and tested for in-vitro skin penetration. All weights are in grams.
  • Figure 1 summarises the trends by plotting miscibility in 100% propylene glycol (actual or extrapolated figures) against FAD type and carbon chain length. The result are exactly as expected.
  • miscibility decreases in the order alcohol > acid > ester reflecting their increasing differense in polarity with propylene glycol.
  • C 14 there is a similar, though less pronounced trend, as the carbon chain becomes more dominant in governing the physicochemistry and the miscibilities of acid and isopropyl ester are very similar.
  • Figures 2 and 3 below show the skin penetration of ibuprofen from Ibugel and the two experimental gel formulations expressed as amount permeated with time and as percentage of dose with time, respectively.
  • the ratio of isopropyl alcohol : water is 30 : 70. This takes account of the water that is part of the 10% NaOH (aq) solution - in l Og of a 10% NaOH solution there is 0.5g and 9.5g water.
  • Ibuprofen aqueous gels and other formulation types based upon them have potential to improve ibuprofen skin penetration and therapeutic effect.
  • formulations of the present application exhibit good tolerance (i.e. reduced irritation and sensitisation) and good ergonomics (ease of use, including packaging).

Abstract

The present invention is directed to a topical formulation comprising (a) an NSAID or a pharmaceutically acceptable salt thereof; (b) a polyhydric alcohol; (c) a C10 - C14 straight chain fatty acid at derivative thereof; (d) a C2 - C4 alcohol; (e) a gelling agent selected from the group consisting of non-ionic polymers; (f) optionally additional pharmaceutically acceptable excipients; and (g) water up to 100 %. The topical formulation has improved skin penetration properties.

Description

Topical Formulation
The present invention relates to a topical pharmaceutical composition having improved skin penetration properties but with aesthetics that meet consumer and patient expectations and ensure compliance. In particular, the present invention relates to such a topical pharmaceutical aqueous gel having improved skin penetration properties which comprises an NSAID.
Transdermal delivery, for local or regional effect of pharmaceutically active compounds, was developed to address the problems associated with orally taken drug formulations, e.g. actives breaking down in the organs in the body such as the liver and without the necessity for the whole body to be treated.
Early technology relied upon the drug being at saturated solubility, often in suspension in the formulation. This is still a very important requirement and enhancer technologies that fail to maintain drug at saturation show little overall increase in skin penetration as solvent enhancer effects are offset by the decrease in drug saturation. As development progressed, drug saturation was generally maintained, but a moderately polar solvent, such as a glycol or glycol ether, was included to increase drug solubility in the stratum corneum barrier layer. Suitable solvents include propylene glycol and Transcutol (diethyleneglycol monoethyl ether). Many known formulations such as Zovirax cream (acyclovir with propylene glycol) and Metosyn (fluocinonide with propylene glycol) use this technology.
Subsequently, development of transdermal technology was driven by the development of patches. The technology maintained the drug at saturation levels and included a moderately polar solvent, but with a lipid enhancer, often a fatty acid, alcohol or ester derivative. As a result, drug solubility in the stratum corneum barrier layer was increased and also drug diffusivity in the stratum corneum barrier layer. As the moderately polar solvent also increased the lipid enhancer solubility in the stratum corneum barrier, and the lipid enhancer also increased the polar solvent diffusivity, synergy was often found with this "co-enhancer" technology. Propylene glycol is an excellent solvent for many drugs and, as discussed, has been widely used to enhance the skin penetration of range of drugs, including antivirals, corticosteroids, testosterone, antihistamines, cardiovasculars and nonsteroidals including ibuprofen. However, propylene glycol, especially at the high concentration required to demonstrate an enhancer effect, is extremely hydroscopic and thus tacky to the touch which limits consumer and patient acceptance and compliance. Although propylene glycol may be replaced by enhancers such as Transcutol or dimethyl isosorbide, these are not as effective and also suffer from poor aesthetics. Propylene glycol is immiscible with many fatty acid derivatives, for example isopropyl myristate, such that the mixture is a two-phase system. This gives rise to the potential for pharmaceutical stability problems and may require the use of surfactant-wax systems to enable formation of emulsions and such like. However, several studies have reported that relatively simple combinations of propylene glycol and isopropyl myristate enhance skin penetration of nicorandil, nefedipine, testosterone and diclofenac sodium.
Totally miscible systems have some potential advantages as co-enhancer systems and studies have been done of propylene glycol with a fatty acid derivative to which a cosolvent, such as Transcutol, is added. However, cosolvent enhancers such as Transcutol or dimethyl isosorbide, are not as effective as propylene glycol in enhancing skin penetration. Without being bound by any theory it is thought that these observations might be the result of a change in driving force for diffusion of the active ingredients following the addition of the penetration modifiers. It is thought that by the addition of Transcutol the solubility of the active ingredients in the formulations containing a permeation modifier was increased to some extent. This increase in solubility results in a reduced thermodynamic activity of the active ingredient and consequently in a smaller driving force for diffusion and therefore a reduced penetration.
WO 02/1 1768 discloses compositions which comprise a fatty alcohol and a diethylene glycol monoalcohol ether. The compositions further include Carbomer as a gelling agent. The lipid enhancers used in combination with propylene glycol include straight chain saturated fatty acid, broadly from C8-C16 and commonly selecting from the fatty acid, fatty alcohol of fatty ester derivatives. Because propylene glycol penetrates into and through the stratum corneum barrier of the skin much faster than fatty acid derivatives, much higher doses of propylene glycol are required, and for optimum effect the fatty acid should be present at around 5% of the dose of propylene glycol. Thus for example, C12-C14 fatty acids isopropyl esters are only miscible at 1-2% of propylene glycol and are not optimised. Conversely, C12 fatty acid alcohol is very miscible with propylene glycol and when present at around 5% of the dose of propylene glycol would itself be at a low degree of saturation which would limit its skin penetration enhancement potential.
The C12-C14 fatty acids, especially the C12 fatty acid, have a further benefit in that they are relatively more soluble in propylene glycol-water, than, for example, the corresponding esters and alcohols. Water-propylene glycol bases are much more acceptable from a cosmetic perspective than propylene glycol alone, but would be expected to have reduced skin penetration due to the reduced propylene glycol concentrations. Niall, this statement is probably true, especially at the pH of Bronson, but I don't know for sure. Of course, as we state, the alcohol is more soluble in propylene glycol. I would leave this in. It is a nice idea and adds to the story.
Ibuprofen is a potent NSAID with moderately good skin penetration. However, the onset, intensity and duration of local analgesic and antiinflammatory activity may be improved by use of skin penetration enhancers, including propylene glycol. However, ibuprofen is a low melting point drug, melting at around 70 degrees centrigrade, and consequently has relatively high solubility in most solvent. For example, Herkenne et al. have shown that the saturated solubility of ibuprofen in propylene glycol is in excess of 40% w/v whereas that in water is only approximately 0.014% w/v. Thus, the use of propylene glycol alone, or in the presense of a low concentration of a fatty acid dervative, such as a C12-C14 fatty acid has the disadvantage that at 5% of ibuprofen (the amount normally contained in topical products) the drug is at a low level of saturation (of approximately l/8th saturation) which serves to reduce the overall skin penetration of ibuprofen from propylene glycol alone-fatty acid systems, such as propylene glycol C12 or C14 fatty acid.
When developing co-enhancer systems there are several parameters which are of significant importance. These are as follows:
- the thermodynamic activity of the drug
- the thermodynamic activity of the fatty acid
- the dose of the fatty acid
- the dose of propylene glycol
It has now been found that addition of water in the presence a volatile solvent will decrease ibuprofen solubility, thus increase the degree of saturation of ibuprofen, such that the true enhancer effect of propylene glycol C12 or C14 fatty acid coenhancer system is restored.
This may need some qualifaction. If all the water and volatile solvent were lost we would be back to the residual phase and with no advantage. It appears that the water perists long after the volatile solvent, and this may be due to hydrogen bonding with propylene glycol. Maybe " Although some water is lost by evaporation, this is a much slower process than that of evaporation of the volatile solvent and is incomplete, believed due to hydrogen bounding to the glycol phase."
Efficient transportation of the active across the skin barrier remains a significant limitation in the development of effective transdermal products.
According to the present invention there is provided a topical formulation comprising:
(a) an NSAID or a pharmaceutically acceptable salt thereof;
(b) a polyhydric alcohol;
(c) a C10-C14 straight chain fatty acid or derivatives thereof including fatty acid esters, fatty alcohols, ethers of fatty alcohols, amides of fatty acids and the like;
(d) a C2- C4 alcohol;
(e) a gelling agent selected from the group consisting of non-ionic polymers;
(f) optionally additional pharmaceutically acceptable excipients; and (g) water up to 100%.
The formulation can be in the form of a gel. The NSAID can be selected from the group consisting of ibuprofen, ketoprofen, flurbiprofen, diclofenac, naproxen. Preferably the NSAID can be selected from ibuprofen, ketoprofen or naproxen.
The polyhydric alcohol is selected from the group consisting of monomeric polyhydric alcohols such as a C2 - C6 glycol, or polymeric polyhydric alcohols such polyethylene glycol, polypropylene glycol or mixtures thereof. The polyhydric alcohol can be propylene glycol or butylene glycol.
The fatty acid is preferably lauric acid, or myristic acid.
A preferred C2 - C4 alcohol is isopropyl alcohol.
The ratio of water: C2 - C4 alcohol is from 90%: 10% to 50%:50%. The ratio of fatty acid to polyhydric alcohol is from 1%:99% to 15%:85%. A preferred ratio is 5%:95% to 10%:90%.
The gelling agent can be selected from hydroxyethyl cellulose, hydroxyeihylmethyl cellulose, hydroxymethylpropyl cellulose, hydroxypropyl cellulose, and polyacrylamide-based gelling agents such as those marketed under the Carbopol brand name. Preferred gelling agents are hydroxypropyl cellulose or hydroxyethyl cellulose.
Typically the optional pharmaceutical excipients include one or more diluents, one or more colourings, pH controlling agents, fillers, flow aids, preservatives, antioxidants, moisture scavengers, colourants and processing aids. A preferred excipient is a pH controlling agent such as an acid or a base. A base such as sodium hydroxide or potassium hydroxide is a preferred pH controlling agent, although any pharmaceutically acceptable base may be used. The compositions can include an additional analgesic agent. Typically, the compositions do not contain pharmaceutically active compounds other than analgesics.
The gel can comprise
(a) 1 - 10% Ibuprofen;
(b) 5 - 50% Propylene glycol or butylene glycol;
(c) up to 15% Laurie acid;
(d) 10 - 30% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent; and
(g) 20 - 60 % Water.
In a preferred embodiment the gel can comprise
(a) 1 - 10% Ibuprofen;
(b) 30 - 50% Propylene glycol or butylene glycol;
(c) 1 - 15% Laurie acid;
(d) 10 - 20% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent; and
(g) 20 - 40 % Water.
In a more preferred embodiment the gel can comprise:
(a) 3 - 7% Ibuprofen;
(b) 35 - 45% Propylene glycol or butylene glycol;
(c) 4 - 6% Laurie acid;
(d) 12 - 15% Isopropyl alcohol;
(e) up to 2% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 1% Sodium hydroxide as pH controlling agent; and
(g) 25 - 35 % Water.
In an alternative embodiment the gel can comprise:
(a) 1 - 10% Ibuprofen;
(b) 5 - 30% Propylene glycol or butylene glycol; (c) up to 3% Laurie acid;
(d) 18 - 30% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent; and
(g) 40 - 60 % Water.
Sensorially active ingredients that stimulate the cold and warm receptors in the skin and artificially produce a cool or warming feeling may also be considered for inclusion. Example of such materials include Menthol and Capsaicin which target cooling and warming receptor respectively and can be used to improve formulation organoleptics. The gel can further comprise up to 10% menthol.
The gel can comprise
(a) l - 10% Ibuprofen;
(b) 30 - 50% Propylene glycol;
(c) 1 - 15% Laurie acid;
(d) 10 - 20% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent;
(g) 20 - 40 % Water; and
(h) up to 10% Menthol.
Typically the composition consists essentially of components (a) to (h). In a preferred embodiment the gel comprises
(a) 3 - 7% Ibuprofen;
(b) 35 - 45% Propylene glycol;
(c) 4 - 6% Laurie acid;
(d) 12 - 15%) Isopropyl alcohol;
(e) up to 2% Hydroxypropylcellulose;
(f) up to 1% Sodium hydroxide;
(g) 25 - 35% Water; and
(h) 0.25 - 3% L-Menthol. In a more preferred embodiment the gel comprises
(a) 5% Ibuprofen;
(b) 42.31% Propylene glycol;
(c) 4.19% Laurie acid;
(d) 13.95% Isopropyl alcohol;
(e) 1.50% Hydroxypropylcellulose;
(f) 0.5% Sodium hydroxide;
(g) 31.55% Water; and
(h) 1.00% L-Menthol.
Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying Figures in which: Figure 1 illustrates the miscibility of FAD in 100% propylene glycol against FAD type and carbon chain length.
Figure 2 illustrates the amount of ibuprofen in μg/cm2 penetrated with time from Ibugel and two experimental formulations one containing hydroxylethyl cellulose (HHX) and one containing hydroxypropyl cellulose (HF); and
Figure 3 illustrates the percentage of dose of applied ibuprofen penetrated with time from Ibugel and two experimental formulations one containing hydroxylethyl cellulose (HHX) and one containing hydroxypropyl cellulose (HF).
The formulations can be made in the following way. For a lOOg batch, propylene glycol (42.3 lg) was added to lauric acid(4.19g) and the resulting mixture was heated (to 60-70°C) while mixing for at least 5 minutes or until a clear solution is formed. Ibuprofen (5.00g) was added with stirring for 5 minutes. Separately an aqueous solution of sodium hydroxide (0.50g) in deionised water (31.55g) was prepared. The aqueous sodium hydroxide solution was added to the propylene glycol/lauric acid mixture, and stirring was continued for a minimum of 5 minutes. A solution of isopropyl alcohol (13.95g) and the hydroxyethyl cellulose (1.50g) was prepared, and to this solution was added menthol with further stirring for a minimum of 10 minutes or until the menthol is dissolved. The resulting isopropyl alcohol/hydroxyethyl cellulose/menthol mixture was added to the solution of aqueous sodium hydroxide, propylene glycol and lauric acid. The combined mixture was gently stirred for a a minimum of 2 hours until a homogeneous mixture was formed.
For smaller batches, such as 20g batches, the amounts are reduced accordingly.
Example formulations Nos 1 & 2 of non-aqueous and an aqueous alcoholic gel are given below in Tables 1 & 2 respectively:
In the embodiment shown below in Table 1 (example 1), the ratio of lauric acid-PG to IPA was chosen as 70:30. Hydroxypropyl cellulose was chosen as a gelling agent for this solvent- rich gel.
Figure imgf000010_0001
Table 1 : Example 1
In Table 2 there is shown an aqueous alcoholic (IPA) gel (example 2) based on Ci2 acid (lauric acid)-PG residual phase.
As examples of formulations prepared using FAD-PG residual phase, it was decided to prepare solvent rich gel (hydroxypropyl cellulose) and an aqueous-IPA gel (hydroxyethyl cellulose). For the hydroxypropyl cellulose gel, a ratio of volatile solvent (IPA) to FAD-PG residual phase of 30-70 was chosen. From this various amount of gel were added and the optimum determined to be 2% hydroxypropyl cellulose. For the hydroxyethyl cellulose gel, a ratio of water-volatile solvent (IPA) to FAD-PG residual phase of 50-50 was chosen. Various ratios of water-IPA were studied to find the maximum water content before phase serration occurred which was 70-30 water-IPA. From this various amount of gel were added and the optimum determined to be 2% hydroxyethyl cellulose gel.
Figure imgf000011_0001
Table 2 : Example 2
Table 3 (examples 3 & 4) shows the actual batch weights and theoretical weights (in brackets) for 20 g nominal batches and tested for in-vitro skin penetration. All weights are in grams.
Figure imgf000011_0002
Table 3 ln-vitro skin penetration studies were conducted where two experimental gel formulations (see table 3) were compared with a commercially available formulation. Both of the experimental gel formulations were statistically significantly superior to the commercially available formulation.
Figure 1 summarises the trends by plotting miscibility in 100% propylene glycol (actual or extrapolated figures) against FAD type and carbon chain length. The result are exactly as expected. For C12, miscibility decreases in the order alcohol > acid > ester reflecting their increasing differense in polarity with propylene glycol. For C14, there is a similar, though less pronounced trend, as the carbon chain becomes more dominant in governing the physicochemistry and the miscibilities of acid and isopropyl ester are very similar.
Figures 2 and 3 below show the skin penetration of ibuprofen from Ibugel and the two experimental gel formulations expressed as amount permeated with time and as percentage of dose with time, respectively.
It is clear that the two experimental gel formulations are significantly superior to Ibugel. Figure 2 shows that ibuprofen skin penetration from lauric acid/PG/hydroxyethyl cellulose is numerically superior (although the difference is not statistically significant) to lauric acid/PG/ hydroxypropyl cellulose. This effect would be unexpected, as the lauric acid/PG/hydroxypropyl cellulose formulation has a higher content of the lauric acid/PG residual phase. However, this may be due to the effect of water increasing the thermodynamic activity of ibuprofen in the aqueous gel.
Additional example embodiments (Nos 5 - 14) are shown in Table below. These examples are prepared in the same way as described previously.
Figure imgf000013_0001
In each of examples 5 - 14 the ratio of isopropyl alcohol : water is 30 : 70. This takes account of the water that is part of the 10% NaOH (aq) solution - in l Og of a 10% NaOH solution there is 0.5g and 9.5g water.
Ibuprofen aqueous gels and other formulation types based upon them have potential to improve ibuprofen skin penetration and therapeutic effect.
The formulations of the present application exhibit good tolerance (i.e. reduced irritation and sensitisation) and good ergonomics (ease of use, including packaging).
Further modifications and improvements can be made without departing from the scope of the invention described herein.

Claims

Claims:
1. A topical formulation comprising:
(a) an NSAID or a pharmaceutically acceptable salt thereof;
(b) a polyhydric alcohol;
(c) a C10-C14 straight chain fatty acid or derivative thereof;
(d) a C2 - C4 alcohol;
(e) a gelling agent selected from the group consisting of non-ionic polymers;
(f) optionally additional pharmaceutically acceptable excipients; and
(g) water up to 100%.
2. A topical formulation as claimed in Claim 1 wherein the NSAID is selected from the group consisting of ibuprofen, ketoprofen, flurbiprofen, diclofenac and naproxen.
3. A topical formulation as claimed in either Claim 1 or Claim 2 wherein the NSAID is selected from ibuprofen, ketoprofen or naproxen.
4. A topical formulation as claimed in any of the preceding Claims wherein the polyhydric alcohol is selected from the group consisting of monomeric polyhydric alcohols such as a C2 - C glycol, or polymeric polyhydric alcohols such as polyethylene glycol, polypropylene glycol or mixtures thereof.
5. A topical formulation as claimed in any of the preceding Claims wherein the polyhydric alcohol can be propylene glycol or butylene glycol.
6. A topical formulation as claimed in any of the preceding Claims wherein the fatty acid is lauric acid, or myristic acid.
7. A topical formulation as claimed in any of the preceding Claims wherein the C2 - C4 alcohol is isopropyl alcohol.
8. A topical formulation as claimed in any of the preceding Claims wherein the ratio of water: C2 - C4 alcohol is from 90%: 10% to 50%: 50%.
9. A topical formulation as claimed in any of the preceding Claims wherein the ratio of fatty acid to polyhydric alcohol is from 1%:99% to 15%:85%.
10. A topical formulation as claimed in Claim 9 wherein the ratio is 5%:95% to 10%:90%.
1 1. A topical formulation as claimed in any of the preceding Claims wherein the gelling agent is selected from hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxymethylpropyl cellulose, hydroxypropyl cellulose, and polyacrylamide-based gelling agents such as those marketed under the Carbopol brand name.
12. A topical formulation as claimed in Claim 11 wherein the gelling agent is hydroxypropyl cellulose or hydroxyethyl cellulose.
13. A topical formulation as claimed in any of the preceding Claims wherein the gel comprises
(a) 1 - 10% Ibuprofen;
(b) 5 - 50% Propylene glycol or butylene glycol;
(c) up to 15% Laurie acid;
(d) 10 - 30% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent; and
(g) 20 - 60 % Water.
14. A topical formulation as claimed in Claim 13 wherein the gel comprises
(a) 1 - 10% Ibuprofen;
(b) 30 - 50% Propylene glycol or butylene glycol;
(c) 1 - 15% Laurie acid;
(d) 10 - 20% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent; and
(g) 20 - 40 % Water.
A topical formulation as claimed in Claim 13 wherein the gel comprises
(a) 3 - 7% Ibuprofen;
(b) 35 - 45% Propylene glycol or butylene glycol;
(c) 4 - 6% Laurie acid;
(d) 12 - 17% Isopropyl alcohol;
(e) up to 2% Hydroxypropyl cellulose or hydroxy ethyl cellulose;
(f) up to 1% Sodium hydroxide as pH controlling agent; and
(g) 25 - 35 % Water.
A topical formulation as claimed in Claim 13 wherein the gel comprises
(a) 1 - 10% Ibuprofen;
(b) 5 - 30% Propylene glycol or butylene glycol;
(c) up to 3% Lauric acid;
(d) 18 - 30% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent; and
(g) 40 - 60 % Water.
A topical formulation as claimed in any of the preceding Claims wherein the formulation further comprises a sensorially active ingredient that stimulate the cold and warm receptors in the skin.
A topical formulation as claimed in Claim 17 wherein the sensorially active ingredient is menthol or capsaicin.
A topical formulation as claimed in Claim 17 or Claim 18 wherein the gel comprises up to 10% menthol.
A topical formulation as claimed in any of Claims 17 - 19 wherein the gel comprises
(a) 1 - 10% Ibuprofen;
(b) 30 - 50% Propylene glycol;
(c) 1 - 15% Laurie acid; (d) 10 - 20% Isopropyl alcohol;
(e) up to 5% Hydroxypropyl cellulose or hydroxyethyl cellulose;
(f) up to 2% Sodium hydroxide as pH controlling agent;
(g) 20 - 40 % Water; and
(h) up to 10% Menthol.
21. A topical formulation as claimed in any of Claims 17 - 20 wherein the gel comprises
(a) 3 - 7% Ibuprofen;
(b) 35 - 45% Propylene glycol;
(c) 4 - 6% Laurie acid;
(d) 12 - 15% Isopropyl alcohol;
(e) up to 2% Hydroxypropylcellulose;
(f) up to 1% Sodium hydroxide;
(g) 25 - 35% Water; and
(h) 0.25 - 3% L-Menthol.
22. A topical formulation as claimed in any of Claims 17 - 21 wherein the gel comprises
(a) 5% Ibuprofen;
(b) 42.31% Propylene glycol;
(c) 4.19% Laurie acid;
(d) 13.95% Isopropyl alcohol;
(e) 1.50% Hydroxypropylcellulose;
(f) 0.5% Sodium hydroxide;
(g) 31.55% Water; and
(h) 1.00% L-Menthol.
23. A topical formulation as claimed in any of Claims 17 - 22 wherein the composition consists essentially of components (a) to (h).
24. A topical formulation as claimed in any of Claims 1 - 22 wherein the composition further includes an additional analgesic agent.
PCT/GB2010/002240 2009-12-11 2010-12-06 Topical formulation WO2011070318A2 (en)

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GB201020601D0 (en) 2011-01-19

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