EP0548145A1 - Composition et traitement a administration topique - Google Patents

Composition et traitement a administration topique

Info

Publication number
EP0548145A1
EP0548145A1 EP91916009A EP91916009A EP0548145A1 EP 0548145 A1 EP0548145 A1 EP 0548145A1 EP 91916009 A EP91916009 A EP 91916009A EP 91916009 A EP91916009 A EP 91916009A EP 0548145 A1 EP0548145 A1 EP 0548145A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
mna
topical
treatment
acceptable salt
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP91916009A
Other languages
German (de)
English (en)
Inventor
M. J. Smithkline Beecham Pharmac. Greenway
P. R. Smithkline Beecham Pharmaceut. Blower
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
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
Publication of EP0548145A1 publication Critical patent/EP0548145A1/fr
Ceased legal-status Critical Current

Links

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.

Abstract

Composition pharmaceutique pour application topique à un mammifère, comprenant de l'acide 6-méthoxy-2-naphthylacétique (MNA) ou un sel pharmaceutiquement acceptable de celui-ci, et un support pharmaceutiquement acceptable.
EP91916009A 1990-09-05 1991-09-05 Composition et traitement a administration topique Ceased EP0548145A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9019413 1990-09-05
GB909019413A GB9019413D0 (en) 1990-09-05 1990-09-05 Topical treatment and composition

Publications (1)

Publication Number Publication Date
EP0548145A1 true EP0548145A1 (fr) 1993-06-30

Family

ID=10681727

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91916009A Ceased EP0548145A1 (fr) 1990-09-05 1991-09-05 Composition et traitement a administration topique

Country Status (9)

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

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9314693D0 (en) * 1993-07-15 1993-08-25 Smithkline Beecham Plc Naphthyl derivatives for treatment method
JP2735392B2 (ja) * 1993-07-28 1998-04-02 ファイザー・インコーポレーテッド 乾癬の治療法
US6113893A (en) * 1993-07-28 2000-09-05 Pfizer Inc. Psoriasis treatment
IN191512B (fr) * 2000-01-21 2003-12-06 Panacea Biotech
DE10250944B9 (de) * 2002-10-31 2004-09-16 Cell Center Cologne Gmbh Verwendung eines Stifts zur Applikation von Pflege- oder Wirkstoffen in die Nase

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
GB8416638D0 (en) * 1984-06-29 1984-08-01 Beecham Group Plc Topical treatment and composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9204019A1 *

Also Published As

Publication number Publication date
ZA916967B (en) 1992-08-26
WO1992004019A1 (fr) 1992-03-19
CA2090974A1 (fr) 1992-03-06
JPH06500778A (ja) 1994-01-27
KR930701993A (ko) 1993-09-08
IE913096A1 (en) 1992-03-11
AU651619B2 (en) 1994-07-28
GB9019413D0 (en) 1990-10-17
AU8494591A (en) 1992-03-30

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