Classifications

• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
• • 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
  • A61K31/28—Compounds containing heavy metals
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12

Definitions

• the present invention pertains to topically applied pharmaceutical compositions of gold compounds and their use in the treatment of psoriasis and as antibacterial agents.
• Elemental gold was believed in ancient times to have various curative properties. However, in the 1960s the effectiveness of simple inorganic gold salts administered intravenously was demonstrated in the treatment of rheumatoid arthritis. Subsequently, aurothiomalate and aurothioglucose administered in parenteral form were found to be more effective. These are water soluble complexes containing approximately 50% of gold by weight and having thiolate ligands. Gold thiopolypeptide has also been injected. Auranofin, a lipid soluble complex containing approximately 29% of gold by weight and having a phosphine and a sulphur ligand, has been administred orally.
• Gold compounds (which term is herein used generally to embrace complexes in which gold is chelated or bound to one or more ligands, organo-gold compounds, inorganic gold compounds and salts thereof) have thus hitherto been administered for therapeutic purposes only by the parenteral or by the oral route and for the treatment of asthma, tuberculosis, pemphigus vulgaris, various forms of arthritis, cancer and infection.
• Gold is a transition state metal that is capable of forming complexes in oxidation states I and III, namely:
• the biological activity of gold compounds is not determined solely by the presence of gold itself but also depends on:- a. the oxidation state (I or III) b. the degree of polymerization c. the types of ligands d. the stereochemistry of the molecule
• Suggested mechanisms for the action of gold drugs include:- a. modulation of humoral and cell-mediated immunity, b. inhibition of the formation of immune complexes and/or the transmitter substances released as a consequence of the immune complex formation, c. inhibition of the formation and/or release of lysosomal enzymes, d. inhibition of the formation and/or action of prostaglandins, e. inhibition of the proliferation of synovial and other cell types including cancer cells, f. modulation of copper and zinc metabolism, g. enzyme inhibition.
• Orally administered auranofin exhibits protracted blood levels of gold in comparison with parentally administered gold compounds and is minimally retained in tissue. Both the parenteral and oral routes of administration have been known to produce severe renal, haematological and other adverse effects including skin and mucuous membrane lesions in some cases. Severe gastrointestinal upsets frequently occur following the use of oral gold.
• synovial membrane particularly when inflamed, may show selective uptake of injected or orally administered gold initially, after which it is distributed to the other tissues.
• auranofin which possesses greater affinity for penetration of lymphocyte membranes than do many other gold compounds, particularly those of the hydrophilic type.
• Brown et al applied a water soluble and a lipid soluble gold complex as a solution in ethanol to the skin of rats in order to measure the levels of gold absorbed into the blood stream through topical application. It was concluded that the lipid soluble complex was more rapidly absorbed into the blood than the water soluble complex and that blood absorption levels were comparable with oral administration. However, no corresponding tests have been reported on human skin, and studies have not shown correlation between blood levels of gold and clinical effectiveness in treatment of any of the foregoing diseases either in rats or in humans. It has now been surprisingly discovered that gold compounds administered topically are in some circumstances significantly more effective than gold compounds administered via parenteral or oral routes while avoiding or ameliorating the disadvantages previously discussed.
• gold compounds administered topically are efficacious in the treatment of local and systemic inflammatory conditions such as psoriasis and rheumatoid arthritis and/or as antibacterial agents.
• gold compounds topically applied act synergistically with corticosteroids in the therapeutic treatment of local inflammatory conditions, particularly psoriasis.
• the present invention therefore resides in the use of topical applications of a gold compound (as hereinbefore defined) to treat local and systemic inflammatory conditions, particularly psoriasis and rheumatoid arthritis.
• the present invention consists in a composition for topical application comprising a gold compound in combination with a pharmaceutically acceptable carrier having viscosity greater than that of water.
• the invention consists in a method for treatment of the inflamed region of a patient suffering from inflammation comprising the step of applying a gold compound to the skin at or in the vicinity of the inflammation.
• the gold compounds used in the present invention are lipid soluble.
• the present invention resides in the synergistic mixture of gold compounds and corticosteroids.
• gold compounds are effective against a range of pathogenic bacteria including gram negative and gram positive bacteria, and particularly effective against gram positive bacteria.
• gold phosphine compounds of the type: R 3 P-Au-Cl, where R is methyl, ethyl, iso-propyl or n-butyl.
• R P-Au-S-R ' gold phosphine compounds of the type: R 3 P-Au-Cl, where R is methyl, ethyl, iso-propyl or n-butyl.
• R is alkyl, alkoxyl or phenyl
• R' is H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted.
• R' moieties include substituted carbohydrates and
• R" is alkyl or H
• R all of which may be the same or different, may be alky, aryl or heterocyclic and may be substituted or unsubstituted.
• a clinically used example is auranofin:
• Preferred compounds for use in the present invention include gold (I) phosphines and related compounds, gold (I) phosphine (or phosphite) thiolates, bis-coordinated gold (I) salts and gold (I) chelates.
• corticosteroid used in conjunction with gold compounds in a preferred embodiment of this invention is betamethasone dipropionate, although other corticosteroids may be equally as effective.
• Suitable pharmaceutical formulations for the application of gold compounds to the skin include liquids, powders, gels, ointments, creams, sprays, including metered aerosol sprays, and patches.
• the choice of formulation depends on the intended therapeutic use.
• the formulation may include stabilizers and/or penetration agents or the like.
• a hydrophobic emulsifiable ointment base produces satisfactory results, however, any other formulation for topical application may be equally applicable, for example monohydric, dihydric and trihydric alkanols.
• the alcohols may be short chain (C, to C, Q ) alcohols or long chain (C,, to C 2Q ) alcohols.
• polyhydric alcohols such as diethylene glycol or glycerol.
• a simple hydrocarbon base is also effective.
• compositions are believed to be efficacious in the alleviation of symptoms of inflammatory disease when applied topically in both humans and animals. It is believed that the compositions are effective at comparatively low concentrations and that therefore the side effects are minimized in comparison with other means of gold administration.
• formulations made in accordance with the present invention may sometimes contain a keratolytic substance, further preferably being salicylic acid.
• a keratolytic substance further preferably being salicylic acid.
• ointments containing heparinoid and hyaluronidase may facilitate absorption of auranofin.
• the base ointment is a wool alcohol ointment or a simple hydrocarbon base.
• Ridaura tablets were ground in a glass mortar and alcohol added. This was allowed to soak for 15 min, then ground for 15 min, by which time most of the alcohol had evaporated. Propylene glycol was added and the mixture ground for a further 10 min. The contents of the mortar were weighed and Ointment of Wool Alcohols added to weight.
• the auranofin powder is triturated with mineral, vegetable or fish oil.
• the ointment base is then added.
• the latter can be a pure hydrocarbon base or can contain emulsifying agents such as wool alcohols.
• adjuncts such as propylene glycol and urea, can facilitate the extent to which the active drug penetrates the skin.
• This formulation gives a final concentration of betamethasone dipropionate of approximately 0.008%.
• compositions containing Auranofin have been exemplified herein, it is proposed that equivalent compositions containing any one, or a combination of the following gold compounds may be equally effective.
• LASONIL is a trade mark of Bayer and contains 5,000 HDBY heparinoid and 15,000 units of hyaluronidase per lOOg ointment.
• DIPROSONE is a trade mark of Schering and contains 0.05%
• the preferred gold (I) phosphines and related compounds have the general formula:
• R is alkyl, aryl or heterocyclic, and may be further substituted; and X is halogen.
• Preferred examples include Et 3PAuCl and
• Ph PAuCl wherein Ph is phenyl and Et is ethyl.
• R is ethyl or phenyl.
• the preferred gold (I) phosphine * (or phosphite) thiolates of the present invention have the general formula:
• R 3PAuSR ID wherein R and R 1 may be H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted.
• Preferred examples include those in which R is ethyl or phenyl, and R 1 is a substituted carbohydrate moiety resulting in compounds such as
• Other examples of appropriate compounds include phosphine or phosphite Au(I) complexes including derivatives of thioalcohols (eg R 3PAuSCH(R 1 )CH(R 2 )OR 3 ), thioacids
• R 3PAuSCH(R 1 )CH(R 2 )COOR 3 thiophenols
• R 3PAuSCoH4R 2 thiophenols
• R 1 , R 2 , R 3 H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted.
• R 2 may be any group eg NH .
• the preferred bis-coordinated gold (I) salts have general formulae of the following type: [R 3PAuPR3 + X " (Ilia)
• the preferred gold (I) chelates have the following formula:
• R is any suitable bridging moiety and may be substituted or unsubstituted alkyl, aryl or heterocyclic;
• X is O, N or S0 2 R 2 and R 1 is H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted.
• R is C 6H4, X is
• auranofin ointment (1.8 mg/g) was applied to a large area of the patient's back and a small area of the left leg. Placebo ointment was applied to the chest and a small area of the right leg. The patient did not know which ointment was active and which was placebo. During the course of one week 80 g of ointment was applied equivalent to 144 mg of auranofin.
• the patient was then treated with a weaker strength ointment but the condition continued to improve.
• the formulation may include stabilizers and/or penetration agents or the like.
• a hydrophobic emulsifiable ointment base produces satisfactory results, however, any .
• other formulation for topical application may be equally applicable, for example monohydric, dihydric and trihydric alkanols.
• the alcohols may be short chain (C ⁇ to C 1Q ) alcohols or long chain (C 12 to C 2Q ) alcohols.
• polyhydric alcohols such as diethylene glycol or glycerol.
• topical auranofin products should be available in at least two strengths, 0.2% and 0.1%. For maximum effectiveness, additional therapeutic agents may be necessary. For example, where there is intense scaling, prior application of a keratolytic agent may be necessary.
• Auranofin has features that could make it a very acceptable topical drug if properly formulated. It appears to be very effective as well as being cosmetically acceptable and much easier and more pleasant to use than many of the conventional therapies. It is not possible to give any indication of the likely incidence of adverse effects based on the limited number of cases studied. However its potential risk would seem to be much less than that of other powerful drugs used in the treatment of psoriasis such as methotrexate and etretinate. It would also seem to be more therapeutically effective than these drugs. Although the corticosteroids can be quite effective in psoriasis, the need, in some patients, to use them on a continuous basis carries the risk of skin atrophy plus undesirable systemic effects to which prolonged use on damaged skin can lead.
• gold compounds other than those exemplified herein may be selected on the basis of their lipid solubility and such compounds, when included in the formulation for topical application, are comprehended within the scope of this invention.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Molecular Biology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dermatology (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• Genetics & Genomics (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Saccharide Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Cited By (11)

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• 1989
  • 1989-03-17 NZ NZ228367A patent/NZ228367A/en unknown
  • 1989-03-20 CA CA000594243A patent/CA1337928C/en not_active Expired - Fee Related
  • 1989-03-22 CH CH4338/89A patent/CH676325A5/fr not_active IP Right Cessation
  • 1989-03-22 JP JP1503937A patent/JPH0725681B2/ja not_active Expired - Fee Related
  • 1989-03-22 AT AT89903664T patent/ATE108655T1/de not_active IP Right Cessation
  • 1989-03-22 EP EP89903664A patent/EP0417105B1/en not_active Expired - Lifetime
  • 1989-03-22 ES ES8901040A patent/ES2021898A6/es not_active Expired - Lifetime
  • 1989-03-22 IE IE89689A patent/IE61381B1/en not_active IP Right Cessation
  • 1989-03-22 DE DE68916958T patent/DE68916958T2/de not_active Expired - Fee Related
  • 1989-03-22 PT PT90085A patent/PT90085B/pt not_active IP Right Cessation
  • 1989-03-22 AU AU34351/89A patent/AU616755B2/en not_active Expired
  • 1989-03-22 WO PCT/AU1989/000118 patent/WO1989009054A1/en not_active Ceased
  • 1989-03-23 GR GR890100183A patent/GR1000698B/el not_active IP Right Cessation
• 1990
  • 1990-09-20 DK DK227090A patent/DK227090D0/da not_active IP Right Cessation
• 1992
  • 1992-06-29 MX MX9203739A patent/MX9203739A/es unknown

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