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WO1992004019A1 - Topical treatment and composition - Google Patents

Topical treatment and composition Download PDF

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Publication number
WO1992004019A1
WO1992004019A1 PCT/GB1991/001509 GB9101509W WO9204019A1 WO 1992004019 A1 WO1992004019 A1 WO 1992004019A1 GB 9101509 W GB9101509 W GB 9101509W WO 9204019 A1 WO9204019 A1 WO 9204019A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
mna
topical
treatment
acceptable salt
Prior art date
Application number
PCT/GB1991/001509
Other languages
French (fr)
Inventor
Michael John Greenway
Peter Robin Blower
Original Assignee
Beecham Group Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group Plc filed Critical Beecham Group Plc
Priority to AU84945/91A priority Critical patent/AU651619B2/en
Priority to KR1019930700658A priority patent/KR930701993A/en
Publication of WO1992004019A1 publication Critical patent/WO1992004019A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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

  • This invention relates to the treatment of inflammation by topical administration and a pharmaceutical composition 5 therefor, two novel salts of 6-methoxy-2-naphthylacetic -acid and a process for making these salts.
  • MNA 6-Methoxy-2-naphthylacetic acid
  • MNA is also mentioned in U.K. Patent Specification No. 20 1,211,134 (Syntex) wherein oral pharmaceutical compositions comprising MNA and a pharmaceutically acceptable carrier and its use in the treatment of inflammation are disclosed.
  • EP-A-0 167 062 discloses topically effective 25 anti-inflammatory pharmaceutical compositions which comprise a compound of the formula (I) :
  • X is a chlorine or bromine atom or a methoxyl, . methylthio or alkyl group of 1-4 carbon atoms
  • MNA 6-methoxy-2-naphthylacetic acid
  • the present invention provides a pharmaceutical composition for topical application to a mammal comprising MNA, or a pharmaceutically acceptable salt thereof, and a topical pharmaceutically acceptable carrier.
  • the present invention further provides a topical pharmaceutical composition for use in the treatment and/or prophylaxis of inflammation which comprises MNA, or a pharmaceutically acceptable salt thereof and a topical pharmaceutically acceptable carrier.
  • the present invention also provides the use of MNA or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis of inflammation by topical administration to mammals, including humans.
  • the present invention also provides a method of treatment or prophylaxis of inflammation in mammals, including humans, comprising topical administration of an anti-inflammatory topically effective amount of MNA or a pharmaceutically acceptable salt thereof.
  • MNA may also form solvates such as hydrates, and the invention also extends to these forms.
  • solvates such as hydrates
  • 'MNA' also includes solvates thereof.
  • MNA can also form salts with bases, such as conventional pharmaceutically acceptable bases.
  • the present invention provides the following novel salts of MNA i.e. 6-methoxy-2-naphthylacetic acid sodium salt and 6- methoxy-2-naphthylacetic acid potassium salt.
  • the present invention also provides a process for the preparation of the sodium or potassium salt which comprises forming a solution of the sodium or potassium salt of MNA respectively and precipitating or isolating the product from solution.
  • the solution of the abovementioned salts may be formed by dissolving the free acid of MNA in an organic solvent and adding sodium ethylhexanoate or potassium ethylhexanoate, respectively.
  • the abovementioned salts may be formed by dissolving the free acid of MNA in a water immisible organic solvent and extracting the MNA as the sodium or potassium salt by extracting into an aqueous solution containing sodium hydroxide or potassium hydroxide respectively.
  • the appropriate salt may then be isolated by precipitation with an appropriate water miscible solvent, such as acetone, or the aqueous solution of the salt may be freeze-dried.
  • MNA or pharmaceutically acceptable salts thereof may be used in the topical treatment of atopic and contact dermatitis, psoriasis, eczema and other inflammatory dermatoses and in inflammatory conditions of eyes, ears, nose and throat. MNA or pharmaceutically acceptable salts thereof, may also be used in the treatment by topical administration of osteo- and rheumatoid arthritis and sprains, strains, tendinitis and bursitis.
  • the amount of MNA or pharmaceutically acceptable salts thereof, present in the formulation should be at least sufficient to maintain an effective concentration at the site of action between applications without showing signs of toxicity. It will be appreciated that the topically effective amount of MNA or a pharmaceutically acceptable salt thereof, will depend on a number of factors such as the nature and severity of the disorder being treated. The optimum concentration of MNA or a pharmaceutically acceptable salt thereof, will depend on its solubility in the formulation and should be at a level exceeding its solubiltiy in order to provide a reservoir and to maintain it at a saturated concentration within the vehicle. A typical formulation suitable for treating an adult human will suitably contain 0.1 to 10% by weight more suitably 0.1 to 3% by weight of MNA or a pharmaceutically acceptable salt thereof.
  • a topical pharmaceutical composition for the method of treatment of the present invention may be administered from 1 to 6 times daily, and more usually from 2 to 4 times daily.
  • compositions of the present invention may be made up in any conventional carriers suitable for the topical administration of anti-inflammatories, for example ointments, creams, lotions, gels, liniments, sprays, gel sticks, patches, films, dressings and aerosols. These are formulated as known in the art, for example as described in standard text books of pharmaceuticals and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, The British Pharmacopoia and United States Pharmacopoeia/ National Formulary.
  • the compositions may also contain, conventional additives such as preservatives and solvents to improve the drug's solubility, and penetration enhancers.
  • a suitable ointment base may conveniently comprise from -65 to 100% (preferably 75 to 96%) of white soft paraffin, from 0 to 15% of liquid paraffin, and from 0 to 7% (preferably 3 to 7%) of lanolin or a derivative or synthetic equivalent thereof.
  • 'soft paraffin' as used above encompasses the cream or ointment bases white soft paraffin and yellow soft paraffin.
  • 'lanolin' encompasses native wool fat and purified wool fat.
  • Derivatives of lanolin include in particular lanolins which have been chemically modified in order to alter their physical or chemical properties and synthetic equivalents of lanolin include in particular synthetic or semisynthetic compounds and mixtures which are known and used in the pharmaceutical and cosmetic arts as alternatives to lanolin and may, for example, be referred to as 'lanolin substitutes'.
  • Softisan 649 is a glycerine ester of natural vegetable fatty acids, of isostearic acid and of adipic acid; its properties are discussed by H. Hermsdorf in Fette, Seifen, Anstrichstoff, Issue No. 84, No.3 (1982),p.p. 3-6.
  • Another suitable ointment base may conveniently comprise a polyethylene - liquid paraffin matrix, for example that available from Squibb under the trade mark 'Plastibase' .
  • a suitable cream base may conveniently comprise an emulsion system, in which two immiscible phases, an aqueous or polar phase and a lipid or oil phase are stabilised by an emulsifying agent (s) (emulsifier) .
  • s emulsifying agent
  • the oil phase of the emulsion may be constituted from known ingredients in a known manner. Whilst the phase may comprise merely an emulsifier (otherwise known as an emulgent) , it is desirably comprised of a mixture of at least one emulsifier with one or more excipients including oils, fats and/or waxes, together with optional film formers and stabilisers as well as thickening and bodying agents.
  • an emulsifier otherwise known as an emulgent
  • excipients including oils, fats and/or waxes, together with optional film formers and stabilisers as well as thickening and bodying agents.
  • an additional hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) make up the so called emulsifying wax, and the wax together with the oil and/or fat make up the so called emulsifying ointment base which "' forms the oil dispersed phase of the emulsions.
  • Topical emulsion formulations may be formulated in a number of ways, all of which depend primarily on the alignment of the emulgent or emulsifying agent and emulsion stabiliser at the oil/water interface, with the non-polar or lipophilic groups soluble in the oil phase and the polar or hydrophilic or lipophobic groups in the aqueous or continuous phase.
  • the more polar hydrophilic emulgents result in oil-in-water emulsions.
  • This principle has been systemised in the idea of a 'hydrophilic-lipophilic balance' (H.LB) Griffen, W. C. J. Soc. Cosmet. Chem.
  • -1- Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include polyoxyethylene sorbitan monostearate (polysorbate 60) , sorbitan monostearate, sorbitan monooleate, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium laury-1 sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Lipophilic substances with relatively high melting points such as beeswax, partial glycerides of capric and caprylic acids, or silicone oil, white soft paraffin or other mineral or vegetable oils are suitable.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol, diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixed ester of 2-ethyl hexanoic acid with a blend of cetyl or stearyl alcohols known as Crodamol CAP may also be used.
  • mono-isoadipate such as di-isoadipate, isocetyl stearate, propylene glycol, diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixed ester of 2-ethyl hexanoic acid with
  • An example of a suitable emulsified system is as follows:- From 5 to 15% cetostearyl alcohol, from 2 to 10% liquid paraffin, from 10 to 20% white soft paraffin, 0.5 to 2.0% carbomer 940, 0.5 to 1.5% sodium lauryl sulphate, 0 to 50% propylene glycol and from 10 to 65% water.
  • a suitable gel base may conveniently comprise a semi-solid system in which a liquid phase is constrained within a three dimensional polymeric matrix with a high degree of cross-linking.
  • the liquid phase may conveniently comprise water, together with from 0 to 50% of water-miscible additives, for example glycerol, polyethylene glycol, ethoxydiglycol, ethanol or propylene glycol, and from 0.1 to 10%, preferably from 0.5 to 2%, of a thickening agent, which may be a natural product, for example tragacanth, pectin, carrageen, agar and alginic acid, or a synthetic or semi-synthetic compound, for example methylcellulose and carboxypolymethylene ('carbopol' ) ; together with one or more preservatives, if required, for example from 0.1 to 2% of methyl 4-hydroxybenzoate ('methyl parabenz') or phenoxyethanol, together with a penetration enhancer such as decylmethyl sulph
  • EP-A-0151953 and EP-A-0272045 may be utilized for preparing topical formulations of MNA or pharmaceutically acceptable salts thereof, and this forms a further aspect of the present invention.
  • compositions of the invention may be produced by conventional pharmaceutical techniques. With MNA, or a pharmaceutically acceptable salt thereof, being added at an appropriate point and ensured that it is well dispersed throughout the formulation.
  • composition may be milled at any suitable stage of the process.
  • compositions of this invention may further contain other therapeutic agents such as anti-infective agents and/or anti-viral agents.
  • Suitable anti-infective agents include the topically applicable antibacterial, anti-yeast and anti-fungal agents already in use in topical anti-inflammatory preparations.
  • anti-viral agents there may be particularly mentioned anti-herpes agents.
  • MNA 6-Methoxy-2-naphthylacetic acid
  • the following ingredients are mixed together in a conventional manner to form a topically effective pharmaceutical composition.
  • Carbomer 940 1.00%
  • Carbomer 940 1.00% Propylene glycol 40.00% Water to 100.00%
  • MNA was administered topically, to the previously shaven flank, two hours prior to carrageenan injection.
  • the area (4 c ⁇ r-) of the flank of the rats was shaven and depilated (Immac) 24 hours prior to drug application.
  • Paw volume was quantified using a mercury plethysmograph 3 hours after carrageenan injection. Paw oedema was taken as the difference in volume of the injected and non-injected paws.
  • Gel base drug formulations were administered topically to the previously shaven flank (nape of neck) , 2 hours prior to carrageenan injection.
  • the gels were applied to the skin (200 ⁇ l) via a syringe and spread over the shaven area using a rubber-tipped applicator.
  • the rats were shaven to expose an area (4cm ⁇ ) of skin at the nape of the neck 24 hours prior to drug application. All animals were housed individually throughout the experiment.
  • Paw volume was quantified using a mercury plethysmograph 3 hours after induction of carrageenan oedema. Paw oedema was taken as the difference in volume of the injected and non- injected paws.
  • Topical formulations of 6MNA Anti-inflammatory activity che carraqeenan-induced rat paw oedema model
  • n 6/group, 200 ⁇ l drug formulation applied to shaven flank (nape of neck) .
  • Values in parenthesis are actual drug concentrations (%) supplied in each gel base formulation.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

A pharmaceutical composition for topical application to a mammal comprising MNA, or a pharmaceutically acceptable salt thereof, and a topical pharmaceutically acceptable carrier.

Description

TOPICAL TREATMENT AND COMPOSITION
This invention relates to the treatment of inflammation by topical administration and a pharmaceutical composition 5 therefor, two novel salts of 6-methoxy-2-naphthylacetic -acid and a process for making these salts.
6-Methoxy-2-naphthylacetic acid (MNA) :
10
Figure imgf000003_0001
(MNA)
15 is disclosed in Jones et. aL, J. A er. Chem. Soc, 70, 2843 (1948) as an intermediate for preparing penicillins.
MNA is also mentioned in U.K. Patent Specification No. 20 1,211,134 (Syntex) wherein oral pharmaceutical compositions comprising MNA and a pharmaceutically acceptable carrier and its use in the treatment of inflammation are disclosed.
EP-A-0 167 062 discloses topically effective 25 anti-inflammatory pharmaceutical compositions which comprise a compound of the formula (I) :
(I)
Figure imgf000003_0002
wherein X is a chlorine or bromine atom or a methoxyl, . methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHR*j_-CH2- or -CR1=CH- group where R-^ is a hydrogen atom or a methyl group and A is a CHOH or CO group, and a pharmaceutically acceptable topically effective carrier.
Figure imgf000004_0001
We have now found that 6-methoxy-2-naphthylacetic acid (MNA) or a pharmaceutically acceptable salt thereof unexpectedly possesses local topical anti-inflammatory activity, and possesses systemic anti-inflammatory activity when administered topically.
Accordingly, the present invention provides a pharmaceutical composition for topical application to a mammal comprising MNA, or a pharmaceutically acceptable salt thereof, and a topical pharmaceutically acceptable carrier.
The present invention further provides a topical pharmaceutical composition for use in the treatment and/or prophylaxis of inflammation which comprises MNA, or a pharmaceutically acceptable salt thereof and a topical pharmaceutically acceptable carrier.
The present invention also provides the use of MNA or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis of inflammation by topical administration to mammals, including humans.
The present invention also provides a method of treatment or prophylaxis of inflammation in mammals, including humans, comprising topical administration of an anti-inflammatory topically effective amount of MNA or a pharmaceutically acceptable salt thereof.
MNA may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'MNA' also includes solvates thereof.
MNA can also form salts with bases, such as conventional pharmaceutically acceptable bases.
The present invention provides the following novel salts of MNA i.e. 6-methoxy-2-naphthylacetic acid sodium salt and 6- methoxy-2-naphthylacetic acid potassium salt.
The present invention also provides a process for the preparation of the sodium or potassium salt which comprises forming a solution of the sodium or potassium salt of MNA respectively and precipitating or isolating the product from solution.
The solution of the abovementioned salts may be formed by dissolving the free acid of MNA in an organic solvent and adding sodium ethylhexanoate or potassium ethylhexanoate, respectively.
Alternatively, the abovementioned salts may be formed by dissolving the free acid of MNA in a water immisible organic solvent and extracting the MNA as the sodium or potassium salt by extracting into an aqueous solution containing sodium hydroxide or potassium hydroxide respectively. The appropriate salt may then be isolated by precipitation with an appropriate water miscible solvent, such as acetone, or the aqueous solution of the salt may be freeze-dried.
MNA or pharmaceutically acceptable salts thereof, may be used in the topical treatment of atopic and contact dermatitis, psoriasis, eczema and other inflammatory dermatoses and in inflammatory conditions of eyes, ears, nose and throat. MNA or pharmaceutically acceptable salts thereof, may also be used in the treatment by topical administration of osteo- and rheumatoid arthritis and sprains, strains, tendinitis and bursitis.
The amount of MNA or pharmaceutically acceptable salts thereof, present in the formulation should be at least sufficient to maintain an effective concentration at the site of action between applications without showing signs of toxicity. It will be appreciated that the topically effective amount of MNA or a pharmaceutically acceptable salt thereof, will depend on a number of factors such as the nature and severity of the disorder being treated. The optimum concentration of MNA or a pharmaceutically acceptable salt thereof, will depend on its solubility in the formulation and should be at a level exceeding its solubiltiy in order to provide a reservoir and to maintain it at a saturated concentration within the vehicle. A typical formulation suitable for treating an adult human will suitably contain 0.1 to 10% by weight more suitably 0.1 to 3% by weight of MNA or a pharmaceutically acceptable salt thereof.
A topical pharmaceutical composition for the method of treatment of the present invention may be administered from 1 to 6 times daily, and more usually from 2 to 4 times daily.
The compositions of the present invention may be made up in any conventional carriers suitable for the topical administration of anti-inflammatories, for example ointments, creams, lotions, gels, liniments, sprays, gel sticks, patches, films, dressings and aerosols. These are formulated as known in the art, for example as described in standard text books of pharmaceuticals and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, The British Pharmacopoia and United States Pharmacopoeia/ National Formulary. The compositions may also contain, conventional additives such as preservatives and solvents to improve the drug's solubility, and penetration enhancers.
A suitable ointment base may conveniently comprise from -65 to 100% (preferably 75 to 96%) of white soft paraffin, from 0 to 15% of liquid paraffin, and from 0 to 7% (preferably 3 to 7%) of lanolin or a derivative or synthetic equivalent thereof.
The term 'soft paraffin' as used above encompasses the cream or ointment bases white soft paraffin and yellow soft paraffin. The term 'lanolin' encompasses native wool fat and purified wool fat. Derivatives of lanolin include in particular lanolins which have been chemically modified in order to alter their physical or chemical properties and synthetic equivalents of lanolin include in particular synthetic or semisynthetic compounds and mixtures which are known and used in the pharmaceutical and cosmetic arts as alternatives to lanolin and may, for example, be referred to as 'lanolin substitutes'.
One suitable synthetic equivalent of lanolin that may be used is the material available under the trade mark 'Softisan' known as 'Softisan 649'. Softisan 649, available from Dynamit Nobel Aktiengesellschaft, is a glycerine ester of natural vegetable fatty acids, of isostearic acid and of adipic acid; its properties are discussed by H. Hermsdorf in Fette, Seifen, Anstrichmittel, Issue No. 84, No.3 (1982),p.p. 3-6.
Another suitable ointment base may conveniently comprise a polyethylene - liquid paraffin matrix, for example that available from Squibb under the trade mark 'Plastibase' .
A suitable cream base may conveniently comprise an emulsion system, in which two immiscible phases, an aqueous or polar phase and a lipid or oil phase are stabilised by an emulsifying agent (s) (emulsifier) .
The oil phase of the emulsion may be constituted from known ingredients in a known manner. Whilst the phase may comprise merely an emulsifier (otherwise known as an emulgent) , it is desirably comprised of a mixture of at least one emulsifier with one or more excipients including oils, fats and/or waxes, together with optional film formers and stabilisers as well as thickening and bodying agents.
Preferably, as explained in more detail below, an additional hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) make up the so called emulsifying wax, and the wax together with the oil and/or fat make up the so called emulsifying ointment base which"' forms the oil dispersed phase of the emulsions.
Topical emulsion formulations may be formulated in a number of ways, all of which depend primarily on the alignment of the emulgent or emulsifying agent and emulsion stabiliser at the oil/water interface, with the non-polar or lipophilic groups soluble in the oil phase and the polar or hydrophilic or lipophobic groups in the aqueous or continuous phase. Thus the more polar hydrophilic emulgents result in oil-in-water emulsions. This principle has been systemised in the idea of a 'hydrophilic-lipophilic balance' (H.LB) Griffen, W. C. J. Soc. Cosmet. Chem. , 1954, 5_, 249 and the various emulgents have been allocated H.L.B. numbers from which their behaviour with constituents of the aqueous and oil phases (to which are applied theoretical required H.L.B. figures) may be predicted. -1- Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include polyoxyethylene sorbitan monostearate (polysorbate 60) , sorbitan monostearate, sorbitan monooleate, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium laury-1 sulphate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Lipophilic substances with relatively high melting points, such as beeswax, partial glycerides of capric and caprylic acids, or silicone oil, white soft paraffin or other mineral or vegetable oils are suitable. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol, diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixed ester of 2-ethyl hexanoic acid with a blend of cetyl or stearyl alcohols known as Crodamol CAP may also be used.
An example of a suitable emulsified system is as follows:- From 5 to 15% cetostearyl alcohol, from 2 to 10% liquid paraffin, from 10 to 20% white soft paraffin, 0.5 to 2.0% carbomer 940, 0.5 to 1.5% sodium lauryl sulphate, 0 to 50% propylene glycol and from 10 to 65% water.
A suitable gel base may conveniently comprise a semi-solid system in which a liquid phase is constrained within a three dimensional polymeric matrix with a high degree of cross-linking. The liquid phase may conveniently comprise water, together with from 0 to 50% of water-miscible additives, for example glycerol, polyethylene glycol, ethoxydiglycol, ethanol or propylene glycol, and from 0.1 to 10%, preferably from 0.5 to 2%, of a thickening agent, which may be a natural product, for example tragacanth, pectin, carrageen, agar and alginic acid, or a synthetic or semi-synthetic compound, for example methylcellulose and carboxypolymethylene ('carbopol' ) ; together with one or more preservatives, if required, for example from 0.1 to 2% of methyl 4-hydroxybenzoate ('methyl parabenz') or phenoxyethanol, together with a penetration enhancer such as decylmethyl sulphoxide.
It should also be appreciated that the supersaturation technology mentioned in EP-A-0151953 and EP-A-0272045 may be utilized for preparing topical formulations of MNA or pharmaceutically acceptable salts thereof, and this forms a further aspect of the present invention.
The other substances mentioned hereinabove as constituents of suitable ointment or cream bases and their properties are discussed in standard reference works, for example pharmacopoeia (hereinabove) .
The compositions of the invention may be produced by conventional pharmaceutical techniques. With MNA, or a pharmaceutically acceptable salt thereof, being added at an appropriate point and ensured that it is well dispersed throughout the formulation.
If necessary the composition may be milled at any suitable stage of the process.
A suitable sterilisation procedure may also be included if necessary. Alternatively raw materials are obtained in sterile condition and the compositions are produced aseptically. The compositions of this invention may further contain other therapeutic agents such as anti-infective agents and/or anti-viral agents. Suitable anti-infective agents include the topically applicable antibacterial, anti-yeast and anti-fungal agents already in use in topical anti-inflammatory preparations. As anti-viral agents, there may be particularly mentioned anti-herpes agents.
6-Methoxy-2-naphthylacetic acid (MNA) may be prepared as described in U.K. Patent No. 1,211,134. (Example 1 , pages 14 to 15) .
The following examples illustrate the topical compositions of the present invention and the pharmacological test illustrates effectiveness of the present invention.
Example 1 (cream)
The following ingredients are mixed together in a conventional manner to form a topically effective pharmaceutical composition.
Cetostearyl Alcohol 7.33%
White soft paraffin 14.11% Liquid paraffin 5.64%
Carbomer 940 1.00%
Sodium lauryl sulphate 0.85%
Propylene glycol 40.00%
MNA 3.00% Water to 100.00%
Example 2 (Gel)
The following ingredients are mixed together in a conventional manner to form a topically effective pharmaceutical composition. MNA 3.00%
Carbomer 940 1.00% Propylene glycol 40.00% Water to 100.00%
Example 3
The following ingredients were mixed together in a conventional manner to form a topically effective pharmaceutical composition.
MNA 0.2%
Ethoxydiglycσl 40.0% Hydroxyethyl cellulose 1.3% Water to 100.0%
Pharmacoloqical Data
1. Method (THF/Methanol as vehicle)
An acute inflammatory response was induced in the right -hind paw of male Wistar rats (Bantin and Kingman, 190-260 gms, n=6 or 8) by sub-plantar injection with 0.1 ml of 1% carrageenan (Viscarin 109) in 0.9% sterile saline.
MNA was administered topically, to the previously shaven flank, two hours prior to carrageenan injection. The drug vehicle, tetrahydrofuran (THF) : methanol (50:50), was applied to the shaven flank (200 μl) of control animals.
The area (4 cπr-) of the flank of the rats was shaven and depilated (Immac) 24 hours prior to drug application.
Paw volume was quantified using a mercury plethysmograph 3 hours after carrageenan injection. Paw oedema was taken as the difference in volume of the injected and non-injected paws.
Results
Figure imgf000013_0001
Vehicle = Tetrahydrofuran (THF) : Methanol (50:50)
Statistically Significant. 2. Method (Gel base as vehicle)
An acute inflammatory response was induced in the right hind paw of male Wistar rats (OLAC, 160-2650 gms, n=6) by sub-plantar injection with 0.1 ml of 1% carrageenan (Viscarin 109) in 0.9% sterile saline.
Gel base drug formulations were administered topically to the previously shaven flank (nape of neck) , 2 hours prior to carrageenan injection. The gels were applied to the skin (200μl) via a syringe and spread over the shaven area using a rubber-tipped applicator.
The rats were shaven to expose an area (4cm^) of skin at the nape of the neck 24 hours prior to drug application. All animals were housed individually throughout the experiment.
Paw volume was quantified using a mercury plethysmograph 3 hours after induction of carrageenan oedema. Paw oedema was taken as the difference in volume of the injected and non- injected paws.
Topical formulations of 6MNA: Anti-inflammatory activity che carraqeenan-induced rat paw oedema model
Formulation: Gel base 1. Propylene glycol (42.1%)
Absolute alcohol (26.3%) Water (31.6%) Gel base 2. Gel base 1 (97.5%) Decylmethyl sulphoxide
(2.5%) Gel base 3. Transcutol (40%)
Water (60%) % Inhibition paw oedema
Gel base (mean +/- sem)
29.32 ± 7.22* (2.50%)
45.65 ± 6.62** 27.69 ± 9.09* (2.50%)
35.87 ± 5.39** (1.50%)
n=6/group, 200μl drug formulation applied to shaven flank (nape of neck) .
Values in parenthesis are actual drug concentrations (%) supplied in each gel base formulation.
Statistically * p = < 0.05 Significant ** p = < 0.01

Claims

-14- Claims
1. A pharmaceutical composition for topical application to a mammal comprising MNA, or a pharmaceutically acceptable salt thereof, and a topical pharmaceutically acceptable - carrier.
2. The use of MNA or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of inflammation by topical administration to mammals, including humans.
3. The use of MNA or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of a medicament for the treatment or prophylaxis of osteoarthritis.
4. The use of MNA or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of a medicament for the treatment or prophylaxis of rheumatoid arthritis.
5. The use of MNA or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of a medicament for the treatment or prophylaxis of sprains and/or strains and/or tendinitis and/or bursitis.
6. A pharmaceutical composition for topical application, according to claim 1, which is in the form of a cream, lotion, liniment, spray, gel stick, patch film, dressing or aerosol.
7. A pharmaceutical composition for topical application according to claim 1 which is in the form of a gel.
8. A pharmaceutical composition for topical application according to claim 7 in which the gel comprises MNA, ethoxydiglycol, hydroxyethyl cellulose and water.
9. A pharmaceutical composition for topical application according to any one of claims 1, 6, 7 or 8 which contains from 0.1 to 3% by weight of MNA.
10. 6-Methoxy-2-naphthylacetic acid sodium salt.
11. 6-Methoxy-2-naphthylacetic acid potassium salt.
12. A process for the preparation of 6-methoxy-2- naphthylacetic acid sodium salt which comprises forming a solution of the sodium salt of 6-methoxy-2-naphthylacetic acid and precipitating or isolating the product from solution.
13. A process for the preparation of 6-methoxy-2- naphthylacetic acid potassium salt wlilch comprises forming a solution of the potassium salt of 6-methoxy-2-naphthylacetic acid and precipitating or isolating the product from solution.
14. A method of treatment and/or prophylaxis of inflammation in mammals comprising topical administration of an anti-inflammatory topically effective amount of MNA or a pharmaceutically acceptable salt thereof.
15. A method of treatment and/or prophylaxis of osteoarthritis in mammals comprising topical administration of an effective amount of MNA or a pharmaceutically acceptable salt thereof.
16. A method of treatment and/or prophylaxis of rheumatoid arthritis in mammals comprising topical administration of an effective amount of MNA or a pharmaceutically acceptable salt thereof.
17. A method of treatment and/or prophylaxis of sprains
5 and/or strains and/or tendinitis and/or bursitis in mammals comprising topical administration of an effective amount of MNA or a pharmaceutically acceptable salt thereof.
18. A topical pharmaceutical composition according to 10 claim 1 for use in the treatment and/or prophylaxis of inflamation, which comprises MNA, or a pharmaceutically acceptable salt thereof, and a topical pharmaceutically acceptable carrier.
15 19. A topical pharmaceutical composition according to claim 1 for use in the treatment and/or prophylaxis of osteoarthritis, which comprises MNA, or a pharmaceutically acceptable salt thereof and a topical' pharmaceutically acceptable carrier.
20
20. A topical pharmaceutical composition according to claim 1 for use in the treatment and/or prophylaxis of rheumatoid arthritis, which comprises MNA, or a pharmaceutically acceptable salt thereof and a topical
25 pharmaceutically acceptable carrier.
21. A topical pharmaceutical composition according to claim 1 for use in the treatment and/or prophylaxis of sprains and/or strains and/or tendinitis and/or bursitis,"
30 which comprises MNA, or a pharmaceutically acceptable salt thereof and a topical pharmaceutically acceptable carrier.
PCT/GB1991/001509 1990-09-05 1991-09-05 Topical treatment and composition WO1992004019A1 (en)

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AU84945/91A AU651619B2 (en) 1990-09-05 1991-09-05 Topical treatment and composition
KR1019930700658A KR930701993A (en) 1990-09-05 1991-09-05 Topical Treatments and Compositions

Applications Claiming Priority (2)

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GB9019413.5 1990-09-05
GB909019413A GB9019413D0 (en) 1990-09-05 1990-09-05 Topical treatment and composition

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EP (1) EP0548145A1 (en)
JP (1) JPH06500778A (en)
KR (1) KR930701993A (en)
AU (1) AU651619B2 (en)
CA (1) CA2090974A1 (en)
GB (1) GB9019413D0 (en)
IE (1) IE913096A1 (en)
WO (1) WO1992004019A1 (en)
ZA (1) ZA916967B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002399A1 (en) * 1993-07-15 1995-01-26 Smithkline Beecham Plc Use of nabumetone or 6-methoxynaphthyl acetic acid for the treatment of dementia
US5747064A (en) * 1993-07-28 1998-05-05 Pfizer Inc. Psoriasis treatment
US6113893A (en) * 1993-07-28 2000-09-05 Pfizer Inc. Psoriasis treatment
WO2001052897A3 (en) * 2000-01-21 2002-03-14 Panacea Biotec Ltd Therapeutic anti-inflammatory and analgesic composition containing selective cox-2 inhibitors
DE10250944B3 (en) * 2002-10-31 2004-06-09 Cell Center Cologne Gmbh Use a pen to apply care or active ingredients to the nose

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US3873718A (en) * 1973-03-29 1975-03-25 Syntex Corp Method for delaying the onset of, or postponing, parturition
US4001301A (en) * 1971-11-04 1977-01-04 Syntex Corporation 6-substituted 2-naphthyl acetic acid derivatives
EP0167062A2 (en) * 1984-06-29 1986-01-08 Beecham Group Plc Topical composition

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US4001301A (en) * 1971-11-04 1977-01-04 Syntex Corporation 6-substituted 2-naphthyl acetic acid derivatives
US3873718A (en) * 1973-03-29 1975-03-25 Syntex Corp Method for delaying the onset of, or postponing, parturition
EP0167062A2 (en) * 1984-06-29 1986-01-08 Beecham Group Plc Topical composition

Non-Patent Citations (1)

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Title
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002399A1 (en) * 1993-07-15 1995-01-26 Smithkline Beecham Plc Use of nabumetone or 6-methoxynaphthyl acetic acid for the treatment of dementia
US5695774A (en) * 1993-07-15 1997-12-09 Smithkline Beecham P.L.C. Use of nabumetone or 6-methoxynaphthyl acetic acid for the treatment of dementia
US5747064A (en) * 1993-07-28 1998-05-05 Pfizer Inc. Psoriasis treatment
US6113893A (en) * 1993-07-28 2000-09-05 Pfizer Inc. Psoriasis treatment
WO2001052897A3 (en) * 2000-01-21 2002-03-14 Panacea Biotec Ltd Therapeutic anti-inflammatory and analgesic composition containing selective cox-2 inhibitors
DE10250944B3 (en) * 2002-10-31 2004-06-09 Cell Center Cologne Gmbh Use a pen to apply care or active ingredients to the nose
DE10250944B9 (en) * 2002-10-31 2004-09-16 Cell Center Cologne Gmbh Use a pen to apply care or active ingredients to the nose

Also Published As

Publication number Publication date
GB9019413D0 (en) 1990-10-17
IE913096A1 (en) 1992-03-11
AU8494591A (en) 1992-03-30
KR930701993A (en) 1993-09-08
EP0548145A1 (en) 1993-06-30
JPH06500778A (en) 1994-01-27
AU651619B2 (en) 1994-07-28
ZA916967B (en) 1992-08-26
CA2090974A1 (en) 1992-03-06

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