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WO1992005769A1 - Prevention ou traitement d'un coup de soleil a l'aide de l'isomere de ketoprofene s(+) - Google Patents

Prevention ou traitement d'un coup de soleil a l'aide de l'isomere de ketoprofene s(+) Download PDF

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Publication number
WO1992005769A1
WO1992005769A1 PCT/US1991/006934 US9106934W WO9205769A1 WO 1992005769 A1 WO1992005769 A1 WO 1992005769A1 US 9106934 W US9106934 W US 9106934W WO 9205769 A1 WO9205769 A1 WO 9205769A1
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Prior art keywords
ketoprofen
weight
composition
mammal
entire composition
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English (en)
Inventor
Abraham Sunshine
Eugene M. Laska
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Bayer Corp
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Miles Inc
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Priority to JP3518339A priority Critical patent/JPH06502174A/ja
Priority to KR1019930700980A priority patent/KR930701977A/ko
Publication of WO1992005769A1 publication Critical patent/WO1992005769A1/fr
Anticipated expiration legal-status Critical
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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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/004—Aftersun preparations
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • 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
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations

Definitions

  • the present invention relates to the use of topically administered S(+) ketoprofen to prevent or treat erythema induced by ultraviolet irradiation in mammalian organisms in need of such prevention or treatment, and to certain topical pharmaceutical compositions comprising unit dosage effective amounts of S(+) ketoprofen.
  • Ketoprofen also known as DL-2-(3-benzoylphenyl) propionic acid, has the structural formula
  • ketoprofen is marketed under the tradename Orudis R .
  • Other tradenames or codenames include RP 19583, Alrheumat, Alrheumun, Capisten, Fastum, Iso-K, Ke enid, Ket ⁇ pron, Lertus, Meprofen, Oruvail and Profenid.
  • Orudis R the drug is available by prescription in the U.S. as capsules containing 25 mg, 50 mg or 75 mg of ketoprofen, indicated for the acute or long-term treatment of the signs and symptoms of rheumatoid arthritis or osteoarthritis.
  • Orudis R is recommended at a daily dose of 150 to 300 mg, divided in three or four doses. It is recommended that drug treatment begin at 75 mg three times or 50 mg four times a day. Small people may need smaller doses. Daily dosages should not exceed 300 mg per day. See also Physician's Desk Reference, 41st edition, 1987, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, NJ 07649, pp. 2179- 2181. For mild to moderate pain and dysmenorrhea, a dose of 25 mg to 50 mg every 6 to 8 hours as needed was recently approved by the Food and Drug Administration ("F.D.A.”) .
  • Food and Drug Administration F.D.A.
  • ketoprofen is a racemic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been a few studies of the individual S(+) and R(-) isomers reported in the literature.
  • the prior art groups the 2-arylpropionic acids together as a class. These possess a chiral center at the carbon atoms alpha to the carboxyl function. According to the prior art, many 2- arylpropionic acids are believed to have a metabolic chiral inversion of their asymmetric center, with partial or complete conversion in nonhuman mammals of the R to the S iso er. The rate and extent of that conversion has been known to vary as noted by Hutt et al, J. Pharm. Pharmacol.. 35, 693-704 (1983). This metabolic inversion of the chiral center, with no other covalent change to the drug, is thus far unique to the 2-arylpropionic acids.
  • Hutt et al "Review - The Metabolic Chiral Inversion of 2-Arylpropionic Acids - A Novel Route with Pharmacological Consequences," J. Pharm. Pharmacol.. Vol. 351, pp. 693-674 at 703 (1983).
  • Hutt et al recognized that evidence existed supporting chiral inverion of the R(-) to the S(+) isomer for ketoprofen.
  • the R-enantiomer of some of these agents may undergo a unique in vivo irreversible inversion to the S-enantiomer.
  • This inversion is not a universal occurrence, as, at least in humans, it does not occur to any significant extent with tiaprofenic acid, indoprofen, carprofen, and perhaps ketoprofen.
  • Jamali et al "Stereoselective Pharmacokinetics of Flurbiprofen in Humans and Rats," Journal of Pharmaceutical Sciences, Vol. 77, No. 8, pp. 666-69 (August 1988) .
  • UV radiation ultraviolet
  • the ultraviolet light alters the keratinocytes in the basal layer of the epidermis.
  • a slight alteration results in erythema, and a severe alteration causes bullae to form from the fluid collected in the epidermis.
  • UV light stimulates the melanocytes in the germinating layer to generate more melanin and oxidizes melanin already in the epidermis. Both of these processes serve as protective mechanisms by diffusing and absorbing additional UV radiation.
  • the effects of the sun on the skin usually begin to appear anywhere from 1 to 24 hours after exposure and range from mild erythema to tenderness, pain, and edema.
  • UV-A (320-400 nm) radiation can cause tanning of the skin, but is weak in causing mild sunburn of the skin. Erythemic activity (producing redness) is relatively weak at this wavelength.
  • the primary action of UV-A is the development of a slow natural tan. At this UV level, radiation produces some immediate pigment darkening.
  • UV-A represents the range in which most photosensitizing chemicals are active. It is also believed that UV-A may augment the effects of UV-B.
  • UV-B (290-320 n ) radiation causes sunburn reaction, which also stimulates pigmentation (tanning) of the skin. It is the most effective UV radiation wavelength for producing erythema, which is why it is called sunburn radiation. It triggers new pigment formation as well as vitamin D production. In addition, it is thought to be responsible for inducing skin cancer.
  • UV-C (200-290 nm) radiation from sunlight does not reach the earth's surface, but artificial UV sources can emit this radiation. It does not tan the - skin, but it can burn it. UV-C radiation from the sun does not reach the surface of the earth. However, UV-C is emitted by artificial ultraviolet sources. Although it will not stimulate tanning, it causes some erythema.
  • Ultraviolet light injury includes epidermal cell death, increase in mitotic index, hyperplasia, as well as the vascular responses of vasodilation, altered permeability and cellular exudation.
  • the vascular changes that occur secondary to exposure to ultraviolet light are biphasic.
  • the immediate erythema reaction is a faint, transient reddening of the skin beginning shortly after exposure to ultraviolet light and fading within 30 minutes after the exposure ends.
  • a delayed erythema reaction appears after 2-6 hours and peaks 10-24 hours after ultraviolet-light exposure. This erythema gradually subsides over the next 2-4 days. Peeling follows 4-7 days after a moderate to severe sunburn.
  • Kinins, histamine, prostaglandins, other vasoactive substances, hydrolytic enzymes, and free radicals have been implicated as mediators of the erythema caused by sunlight.
  • Prostaglandins have been shown to increase in erythematous skin exposed to ultraviolet B radiation.
  • Aspirin and indomethacin which are nonsteroidal anti- inflammatory agents have been shown to inhibit the prostaglandin synthetase system in skin.
  • Snyder et al "Intradermal Anti-Prostaglandin
  • nonsteroidal anti-inflammatory drugs have been administered orally to human subjects and have been demonstrated to be effective in reducing erythema after exposure to ultraviolet radiation.
  • Edwards et al "Reduction of the Erythema Response to Ultraviolet Light by Nonsteroidal Anti-inflammatory Agents," Arch. Dermatol. Res. , Vol. 272, pp. 263-267, studied the effect of orally administered aspirin, indomethacin and ibuprofen on ultraviolet B induced erythema in human subjects. All three drugs were comparable in reducing the sunburn response to ultraviolet radiation.
  • S(+) ketoprofen can be advantageously topically administered to mammals, especially humans, to prevent or treat ultraviolet radiation-induced erythema and to evoke such prevention or treatment more effectively than possible by administration of the same dose of ketoprofen in its racemic form.
  • S(+) ketoprofen is more potent than an equal amount of the racemic mixture.
  • the present invention thus provides a method for preventing ultraviolet radiation- induced erythema in a mammal, said method comprising topically administering to a mammal exposed to ultraviolet radiation an amount effective to prevent ultraviolet radiation of S(+) ketoprofen substantially free of R(-) ketoprofen.
  • the present invention provides a method for treating ultraviolet radiation- induced erythema in a mammal, said method comprising topically administering to a mammal in need of such treatment an amount effective to treat ultraviolet radiation-induced erythema of S(+) ketoprofen substantially free of R(-) ketoprofen.
  • the present invention provides a pharmaceutical composition of matter for use in preventing or treating ultraviolet radiation-induced erythema in mammals, especially humans, said composition comprising an amount effective to prevent or treat ultraviolet radiation-induced erythema of S(+) ketoprofen substantially free of R(-) ketoprofen.
  • S(+) ketoprofen is associated with a nontoxic topical pharmaceutically acceptable inert carrier or diluent therefor.
  • ketoprofen or “racemic ketoprofen” as used herein is intended to encompass not only DL-2- (3-benzoylphenyl)propionic acid itself but also any pharmaceutically acceptable salt thereof.
  • S(+) ketoprofen as used herein is intended to encompass not only the dextrorotatory or S(+) isomer of 2-(3-benzoylphenyl)propionic acid but also any pharmaceutically acceptable, antierythematously effective salt thereof.
  • substantially free of R(-) ketoprofen as used in conjunction with the term "S(+) ketoprofen” means that the S(+) ketoprofen is sufficiently free of R(-) ketoprofen [which is the levorotatory form or R(-) isomer of 2-(3-benzoylphenyl)-propionic acid or salt thereof] to exert the desired antierythema effect.
  • R(-) ketoprofen which is the levorotatory form or R(-) isomer of 2-(3-benzoylphenyl)-propionic acid or salt thereof
  • the active ingredient should contain at least 90% by weight S(+) ketoprofen and 10% or less by weight R(-) ketoprofen.
  • the weight ratio of S(+) ketoprofen to R(-) ketoprofen is greater than or equal to 20:1, more preferably greater than 97:3.
  • the S(+) keto ⁇ profen is 99 or more % by weight free of R(-) ketoprofen, i.e., the weight ratio of S to R is approximately equal to or greater than 99:1.
  • a 20:1 ratio of S(+) to R(-) is readily obtainable from racemic ketoprofen by literature methods and eminently useful in the practice of the present invention.
  • specific amounts of S(+) ketoprofen are set forth below, it should be understood that, unless otherwise specified, the amounts are given in mg of the acid, not of a salt.
  • the amounts given represent total ketoprofen content, most of which is in the S(+) form.
  • "50 mg S(+) ketoprofen” means 50 mg total ketoprofen at least 90% of which is in the S(+) form, preferably at least 95%, more preferably at least 97% and most preferably 99% or more.
  • Topical S(+) ketoprofen in accord with the present invention, produces the following unexpected results:
  • ketoprofen is more potent than racemic ketoprofen for topical administration on a mammal since the ketoprofen is substantially, or in large part, in the active form;
  • the R(-) isomer in the case of ketoprofen, the R(-) isomer is not active and would not substantially overcome the effects of ultraviolet-induced erythema or sunburn because there would probably be little if any chiral conversion in the skin.
  • S(+) ketoprofen applied in the same amount as racemic ketoprofen would provide a better response for preventing or treating ultraviolet radiation-induced erythema.
  • S(+) ketoprofen would be at least twice as potent.
  • the precise amount of topical S(+) ketoprofen for use in accord with the present invention will vary depending, for example, on the size and kind of the mammal and the condition for which the drug is administered.
  • the amount effective to prevent or treat ultraviolet radiation-induced erythema of S(+) ketoprofen will typically be from about 0.5 wt. % to about 10 wt. % although greater amounts (e.g., 15 wt.
  • the preferred composition contains about 1 wt. % to about 5 wt. %, more preferably about 2.5 to 3.5 wt. % ketoprofen. The most preferred composition would likely contain about 3.0 wt. % ketoprofen. It should be noted, however, that lesser amounts may be useful on patients with particularly sensitive skin and/or on the skin of children.
  • the S(+) ketoprofen of the present invention may be applied in any vehicle or in any fashion suitable for topical administration. Topical preparations typically include solutions, .e.g. , clear or milky lotions, gels, creams, ointments, sprays, lip balm, clothwipe, impregnated bandages and other topical and transdermal delivery devices.
  • Suitable solvents or vehicles, for instance, for the topical S(+) ketoprofen composition of the present invention includes methanol, ethanol, propyl alcohol, acetone, n-butyl alcohol, isobutyl alcohol and the like.
  • sunscreens are to prevent sunburn and aid in the development of a tan. Secondarily, they serve to protect exposed areas of the body in susceptible individuals from the long-term hazards of skin cancer and premature aging. In addition, sunscreens can be used to protect against drug-related ultraviolet-induced photosensitivity.
  • sunscreen agent shall refer to the use of S(+)- ketoprofen as a sunscreen-sunburn preventive agent, a sunscreen-suntanning agent and/or a sunscreen-opaque sunblock agent.
  • S(+)- ketoprofen as a sunscreen-sunburn preventive agent, a sunscreen-suntanning agent and/or a sunscreen-opaque sunblock agent.
  • a sunscreen-sunburn preventive agent contains an active ingredient that absorbs 95% or more of the radiation in the ultraviolet range at wavelengths from 290-320 nm and thereby removes the sunburning rays;
  • a sunscreen-suntanning agent contains an active ingredient that absorbs at least 85% of the radiation in the ultra-violet range at wavelengths from 290-320 nm, but transmits ultraviolet wavelengths longer than 320 nm (such agents permit tanning in the average individual and also permits some erythema without pain) ;
  • a sunscreen-opaque sunblock agent has an opaque agent that reflects or scatters all radiation in the ultraviolet and visible range from 290-777 nm and thereby prevents or minimizes suntan and sunburn.
  • topical ingredients are present in commercial sunscreens or sunblocks: titanium dioxide, petrolatum, red petrolatum, benzophenone-3, isopropyl myristate, aloe vera extract, synthetic beeswax, cetyl palmitate, ceresin, lanolin, cetyl alcohol, alcohol, oleth-3 phosphate, synthetic spermaceti, glycerin, mineral oil, lanolin alcohol, cetyl stearyl glycol, lanolin oil, triethanolamine, carbomer 934, benzyl alcohol, menthol, camphor, essential oils, acrylic-acrylate copolymer, ammonium hydroxide, carbomer 934P, dimethicone, quaternium-15, stearic acid, stearyl alcohol, water, xanthan gum, SD alcohol 40, animal protein derivative, hydroxyethyl cellulose, choleth-24, hydroxypropyl cellulose, PPG-15 stearyl ether, propylene glyco
  • sunscreens should be applied approximately 30 minutes before exposure to the sun. However, there are exceptions, for instance, aminobenzoic acid and its esters are more effective if applied two hours before exposure.
  • Pre-application of the topical S(+) ketoprofen composition prior to sun exposure to the skin is advantageous because it allows the S(+) ketoprofen to penetrate and perhaps bind with the skin.
  • the amount of S(+) ketoprofen useful in the topical preparations of the present invention is an amount sufficient to prevent or treat ultraviolet radiation-induced erythema.
  • Typical unit dosage forms for topical administration will contain about 0.5 wt. % to about 10 wt. %, preferably about 1 wt. % to about 5 wt. %, most preferably about 2.5 wt. % to about 3.5 wt. %, S(+) ketoprofen based on the entire weight of the composition per topical unit dose application. If the composition is intended for sustained release such as by using microcapsules or microspheres, much larger amounts of the active ingredient would of course be incorporated into an individual unit. As noted earlier, the composition and the method of the present invention is "substantially free of the R(-) ketoprofen.”
  • the topical S(+) ketoprofen composition of the present invention may further be combined with other types of sun-protective and/or antierythema topical agents.
  • Such agents may absorb 95 percent or more of the ultraviolet B radiation and thereby prevent or minimize the deleterious effects on human skin caused by excessive exposure to ultraviolet B (290 to 320 nm) and ultraviolet A (320 to 400 nm) radiation. Protection is afforded by the active chemical ingredients of a sunscreen through absorption, reflection and scattering of solar radiation impinging on the skin.
  • Topical sunscreens can fall within one of two categories: (1) chemical, and (2) physical sunscreens.
  • Chemical sunscreens contain one or more UV-absorbing chemicals, and upon application of a thin and invisible film, act as filters and do not allow the penetration of ultraviolet radiation to the viable cells of the epidermis. Chemical sunscreens are usually colorless because they do not contain any visible light-absorbing chemicals and are, therefore, cosmetically acceptable to most persons provided they are a nonirritant to the skin and eyes, nonphotosensitizing, stable, nonvolatile, and nonstaining to skin and clothes. Most of the commercial topical sunscreens contain one or more ultraviolet B absorbing chemicals in a moisturizing base. More recently, many leading brand-name sunscreens also contain ultraviolet A absorbing chemicals, especially the different benzophenones. The most widely used chemical sunscreens contain para- aminobenzoic acid (PABA) , PABA esters (a yldimethyl)
  • the formulation base (vehicle) used include alcohol plus glycerol or glycol, oil-in-water or water-in-oil lotion, cream, or ointment.
  • vehicle in which the ultraviolet radiation absorbing chemical is incorporated can determine whether a sunscreen remains effective under the general use condition involving prolonged sunbathing, sweating (sporting activities) , and swimming.
  • This adherent property to skin known as "substantivity,” varies considerably among commercially available sunscreen formulations, some of which are retained on the skin and others of which are washed off easily after sweating or swimming.
  • Table 2 identifies several commercial chemical sunscreen preparations along with their ingredients and type of composition.
  • PABA-ester combination sunscreens :
  • Non-PABA sunscreens are non-PABA sunscreens:
  • Physical sunscreens are usually opaque formulations and contain ingredients particulate in nature that do not selectively absorb ultraviolet radiation, but, when applied as a thin film, primarily reflect and scatter ultraviolet and visible radiation because of the size of the particles and the thickness of the film.
  • ingredients particulate in nature that do not selectively absorb ultraviolet radiation, but, when applied as a thin film, primarily reflect and scatter ultraviolet and visible radiation because of the size of the particles and the thickness of the film.
  • These include titanium dioxide (5% to 20%) , talc (magnesium silicate) , magnesium oxide, zinc oxide, kaolin, ferric chloride, and ichthyol (ichthammol) .
  • Zinc oxide appears to be the most effective.
  • Physical sunscreens are, however, essential for those patients who are unusually sensitive to ultraviolet radiation as well as visible radiation; these are usually applied to limited areas such as the nose, lips, or helix of the ear.
  • Table 3 identifies several commercial physical sunscreen preparations along with their ingredients and type of composition.
  • S(+) ketoprofen may be combined along with any of the compounds identified in any of the Tables identified above as a topical vehicle for administration.
  • suntan products differ from sunscreens only by having a lower concentration of the sunscreen agent.
  • concentration of the active ingredient is an important factor in judging the use and effectiveness of a product.
  • SunDare Lotion a suntan product, contains 1.75% cinoxate
  • Maxafil Cream a sunscreen product, contains 4% (about twice as much as the suntan product) and 5% menthyl anthranilate, a second sunscreen.
  • the sunburn/sunscreen product of the present invention may include a burn or sunburn treatment component such as an anesthetic, antimicrobial or another ingredient.
  • the anesthetic component of commercial products presently include: benzocaine, lidocaine hydrochloride, buta ben picrate, dibucaine, tetracaine hydrochloride, tripelennamine, and menthol benzocaine.
  • the antimicrobial component of commercial products currently include: benzethonium chloride, benzalkonium chloride, povidone-iodine, chloroxylenol, chlorobutanol, 8-hydroxyquinoline, phenol, 8-hydroxyquinoline sulfate, cresol-camphor complex, chlorothymol, methylbenzethonium chloride, triclosan, benzyl alcohol, and parahydracin.
  • the S(+) ketoprofen for use in the method and compositions of the present invention can be prepared by a variety of methods, such as by resolution of racemic ketoprofen.
  • Farge et al United States Patent No. 3,641,127 describes the preparation of racemic ketoprofen and related compounds; see, in particular, Example V thereof.
  • the Farge et al patent also describes a method for preparing the individual D- and L-isomers by oxidation of the corresponding optically active (3-benzylphenyl) ' alkanoic acids; see column 3, lines 22-40.
  • HPLC methods other than Sallustio et al's for resolving enantiomers of NSAID's such as ketoprofen and fenoprofen, and likely adaptable to resolution of ketoprofen include the method of Doyle et al, Phar . Technol. 9 2) . 28-32 (1985) , which utilizes conversion of the race ate to its amide derivatives for effective resolution; and that of Wainer et al, J. Chromatogr. 284fl) , 117-124 (1984) , which utilizes conversion of the drug to 1-naphthalenemethylamide derivatives.
  • Singh et al's method is a new version of the second approach, using optically active amphetamine as the resolving agent, followed by separation of the diastereoisomers by capillary gas chromatography with nitrogen-phosphorus detection.
  • the acid now in optically pure form, could of course then be regenerated from the salt as is well-known.
  • the usual method in the art- utilizes optically active ⁇ -methylbenzylamine and involves preparation of the diastereoisomeric NSAID- ⁇ -methylbenzylamide directly by means of a coupling agent (e.g. 1,1'- carbonyldiimidazole) or via the NSAID acid chloride (prepared with thionyl chloride) .
  • a coupling agent e.g. 1,1'- carbonyldiimidazole
  • NSAID acid chloride prepared with thionyl chloride
  • the S(+) isomer can be separated from racemic ketoprofen by preparing a salt of ketoprofen with an alkaloid or similar resolving agent such as cinchonidine, then separating the products by fractional crystallization from a solvent in which the dextrorotatory isomer is least soluble. The d-salt can then be acid cleaved to yield S(+) ketoprofen.
  • Alvarez United States Patent No. 3,637,767, issued January 25, 1972, which relates to resolution of naproxen and related compounds
  • Kaiser et al J. Pharm. Sci. 65(21 r 269-273 (1976) , which relates to resolution of ketoprofen.
  • S(+) ketoprofen may be conveniently obtained by resolution of racemic ketoprofen, it may also be possible to utilize a chemical or microbiological synthetic process which will provide the S(+) enantiomer directly.
  • a chemical or microbiological synthetic process which will provide the S(+) enantiomer directly.
  • One such chemical process is described in Farge et al. United States
  • Patent No. 3,641,127 as already mentioned hereinabove.
  • Another chemical process is provided by Schloemer, United States Patent No. 4,542,237, which describes a process for preparing ⁇ -arylalkanoic acids utilizing novel a-hydroxy alkyl aryl ketals as intermediates.
  • the process is advantageous in that the ⁇ -hydroxy ketal can be resolved by well-known methods and the optically active ⁇ -hydroxy ketal thus obtained can then be used in the subject process to ultimately afford the desired acid in optically pure form.
  • a pharmaceutically active salt or ester thereof which most preferably is naproxen or ketoprofen but which may be ketoprofen or various other NSAIDs, is prepared in stereospecific form by subjecting a compound of the formula
  • the desired acid is obtained having at least 70% by weight in the S-configuration.
  • a microorganism is selected such that the acid which is formed is at least 90% by weight in the S-configuration.
  • Use of this method has afforded naproxen with enantiomeric distributions of 98.9% S and 1.1% R in one instance, and distributions of 99.5% S and 0.5% R in another. Processes of this type may be utilized to prepare S(+) ketoprofen for use in the present invention if the S(+) isomer can be obtained in sufficient purity [ideally, at least 90% by weight S(+) isomer.]
  • S(+) ketoprofen When S(+) ketoprofen is to be employed in the form of a pharmaceutically acceptable, antierythematously active salt thereof, such salt may be conveniently prepared by direct salification of S(+) ketoprofen by known methods. See, for example, deVincentiis, United States Patent No. 4,440,787, which describes salts of (2• ,4'-difluoro-4-biphenyl)oxypro- pionic acid with metallic ions, such as sodium, potassium, magnesium and calcium, or with pharmaceutically acceptable organic bases, such as lysine, arginine and diethanolamine. Compare also Ar itage et al, United States Patent No.

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Abstract

Il est possible de prévenir ou de traiter un érythème dû à des rayonnements ultraviolets chez un mammifère humain ayant besoin d'une telle prévention ou d'un tel traitement, c'est-à-dire un mammifère souffrant d'un coup de soleil ou cherchant à en éviter un, par administration topique d'une quantité efficace posologique unitaire de l'énantiomère de kétoprofène S(+) permettant de prévenir ou de traiter un érythème, ledit énantiomère étant sensiblement exempt de son antipode de kétoprofène R(-).
PCT/US1991/006934 1990-10-05 1991-09-27 Prevention ou traitement d'un coup de soleil a l'aide de l'isomere de ketoprofene s(+) Ceased WO1992005769A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP3518339A JPH06502174A (ja) 1990-10-05 1991-09-27 ケトプロフェンのｓ（＋）異性体を用いての日焼けの予防又は処理
KR1019930700980A KR930701977A (ko) 1990-10-05 1991-09-27 케토프로펜의 s(＋) 이성질체를 이용한 일조화상(日照火傷)의 예방 및 치료

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US59387290A 1990-10-05 1990-10-05
US593,872 1990-10-05

Publications (1)

Publication Number Publication Date
WO1992005769A1 true WO1992005769A1 (fr) 1992-04-16

Family

ID=24376552

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/006934 Ceased WO1992005769A1 (fr) 1990-10-05 1991-09-27 Prevention ou traitement d'un coup de soleil a l'aide de l'isomere de ketoprofene s(+)

Country Status (6)

Country Link
EP (1) EP0552289A4 (fr)
JP (1) JPH06502174A (fr)
KR (1) KR930701977A (fr)
AU (1) AU8903591A (fr)
CA (1) CA2093359A1 (fr)
WO (1) WO1992005769A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2804024A1 (fr) * 2000-01-21 2001-07-27 Menarini France Nouvelles compositions pharmaceutiques a action anti- inflammatoire et leur procede de preparation
EP1234573A1 (fr) * 2001-02-22 2002-08-28 Menarini France S.A. Nouvelles compositions pharmaceutiques à action anti-inflammatoire et leur procédé de préparation
US6599531B2 (en) 1996-06-12 2003-07-29 Knoll Pharmaceutical Company Method of making ibuprofen and narcotic analgesic compositions
WO2004082580A3 (fr) * 2003-03-18 2005-01-27 Berlin Chemie Ag Formulations topiques stabilisees contenant du ketoprofene
EP1688129A1 (fr) * 2005-02-02 2006-08-09 ACO Hud AB Nouvelle préparation thérapeutique
US11179345B2 (en) 2016-10-12 2021-11-23 Teikoku Seiyaku Co., Ltd. Water-based adhesive patch

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US3019165A (en) * 1958-05-09 1962-01-30 Edgewood Lab Inc Sunburn preventive and burn remedy
US3068153A (en) * 1958-11-13 1962-12-11 Union Carbide Corp Sunburn preventive compositions
US3275520A (en) * 1962-05-29 1966-09-27 Gen Aniline & Film Corp Methods for protecting the skin against actinic radiations
US4393076A (en) * 1980-05-14 1983-07-12 Hisamitsu Pharmaceutical Co., Inc. Anti-inflammatory and analgesic gel composition

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DE3707532C2 (de) * 1987-03-09 1998-05-28 Bauer Johann Verwendung einer Kombination von Extr. Gingko biloba oder mindestens einem Gingkolid und Acetylsalicylsäure oder DL-Lysin-mono-acetylsalicylat oder Diflunisal zur Behandlung von Verbrennungen, Verbrühungen, Strahlenschäden und Erfrierungen
ES2067754T5 (es) * 1989-08-17 1998-10-01 Sepracor Inc Composicion bucal que contiene s(+) flurbiprofeno o ketoprofeno.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3019165A (en) * 1958-05-09 1962-01-30 Edgewood Lab Inc Sunburn preventive and burn remedy
US3068153A (en) * 1958-11-13 1962-12-11 Union Carbide Corp Sunburn preventive compositions
US3275520A (en) * 1962-05-29 1966-09-27 Gen Aniline & Film Corp Methods for protecting the skin against actinic radiations
US4393076A (en) * 1980-05-14 1983-07-12 Hisamitsu Pharmaceutical Co., Inc. Anti-inflammatory and analgesic gel composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0552289A4 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6599531B2 (en) 1996-06-12 2003-07-29 Knoll Pharmaceutical Company Method of making ibuprofen and narcotic analgesic compositions
FR2804024A1 (fr) * 2000-01-21 2001-07-27 Menarini France Nouvelles compositions pharmaceutiques a action anti- inflammatoire et leur procede de preparation
EP1234573A1 (fr) * 2001-02-22 2002-08-28 Menarini France S.A. Nouvelles compositions pharmaceutiques à action anti-inflammatoire et leur procédé de préparation
WO2004082580A3 (fr) * 2003-03-18 2005-01-27 Berlin Chemie Ag Formulations topiques stabilisees contenant du ketoprofene
RU2340335C2 (ru) * 2003-03-18 2008-12-10 Менарини Ричерке С.П.А. Стабилизированные композиции для местного применения, содержащие кетопрофен
EP1688129A1 (fr) * 2005-02-02 2006-08-09 ACO Hud AB Nouvelle préparation thérapeutique
NO339644B1 (no) * 2005-02-02 2017-01-16 Omega Pharma Innovation & Dev Nv Ny terapeutisk formulering
US11179345B2 (en) 2016-10-12 2021-11-23 Teikoku Seiyaku Co., Ltd. Water-based adhesive patch
EP4218741A1 (fr) * 2016-10-12 2023-08-02 Teikoku Seiyaku Co., Ltd. Timbre adhésif à base d'eau contenant du ketoprofen

Also Published As

Publication number Publication date
CA2093359A1 (fr) 1992-04-06
KR930701977A (ko) 1993-09-08
EP0552289A1 (fr) 1993-07-28
AU8903591A (en) 1992-04-28
JPH06502174A (ja) 1994-03-10
EP0552289A4 (en) 1993-08-11

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