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WO1992005768A1 - Prevention ou traitement de coups de soleil au moyen de l'isomere s(+) de flurbiprofene - Google Patents

Prevention ou traitement de coups de soleil au moyen de l'isomere s(+) de flurbiprofene Download PDF

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Publication number
WO1992005768A1
WO1992005768A1 PCT/US1991/006881 US9106881W WO9205768A1 WO 1992005768 A1 WO1992005768 A1 WO 1992005768A1 US 9106881 W US9106881 W US 9106881W WO 9205768 A1 WO9205768 A1 WO 9205768A1
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Prior art keywords
flurbiprofen
weight
composition
mammal
entire composition
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PCT/US1991/006881
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English (en)
Inventor
Abraham Sunshine
Eugene M. Laska
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Analgesic Associates
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Publication of WO1992005768A1 publication Critical patent/WO1992005768A1/fr

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    • 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
    • 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
    • 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

Definitions

  • the present invention relates to the use of topically administered S(+) flurbiprofen 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(+) flurbiprofen.
  • Flurbiprofen also known as ( ⁇ )-2-fluoro- ⁇ - methyl-[l,l '-biphenylj-4-acetic acid, as ( ⁇ ) -2-fluoro- ⁇ - methyl-4-biphenylacetic acid or as ( ⁇ ) -2-(2-fluoro-4- biphenylyl)propionic acid, is described in U.S. Patent No. 3,755,427 and has the structural formula:
  • the compound is well-known as a nonsteroidal anti- inflammatory drug having analgesic and antipyretic activity.
  • Flurbiprofen is not yet marketed in the United States, but has been on the market in numerous countries overseas, including Europe, for a number of years. Tradenames and codenames by which it is known include Ansaid, Cebutid, Froben, BTS 18322 and U-27182.
  • Froben the drug is available abroad as tablets containing 50 or 100 mg of flurbiprofen.
  • For rheumatic disorders such as rheumatoid arthritis, it is recommended at a daily dose of 150 to 200 mg in divided doses of two to four per day, increased to a daily dose of 300 mg in acute conditions.
  • Flurbiprofen has been found useful in controlling acute and chronic pain, including that associated with ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, postsurgical dental pain, postsurgical gynecological pain, postpartum uterine pain, primary dysmenorrhea, cancer pain, the pain of acute gout and the pain of acute bursit s/tendinitis of the shoulder. See The American Journal of Medicine.
  • flurbiprofen is a race ic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been a few isolated studies of the individual S(+) and R(-) iso ers reported in the literature. These reflect that the S(+) enantiomer, analogously to other 2-arylpropionic acids, is the active form of flurbiprofen.
  • Hutt et al reported that, in contrast, for several other 2-arylpropionic acids, the inactive R(-) isomer was not converted jLn vivo to the active S(+) isomer as readily as iubuprofen, although the conversion seemed to occur to some extent over time. Naproxen, they noted, has been the only compound marketed as the S(+) enantiomer to date. Hutt et al concluded:
  • Hutt et al indicated that flurbiprofen had an S(+)/R(-) activity ratio .in vivo of 878 and in vitro 2-16; the jLn vitro study involved antagonism of rat SRS-A on the tracheal chain of guinea pigs and the in vivo study assessed guinea pig anaphylaxis.
  • the reference cited by Hutt et al for the flurbiprofen studies was Greig et al, J__ Med. Chem. 18. 112-116 (1975) .
  • Greig et al who were associated with the Upjohn Company, one of the developers of flurbiprofen, studied the antagonism of slow reacting substance in anaphylaxis (SRS-A) and other spasmogens on the guinea pig tracheal chain by hydrotropic acids. Greig et al also studied the ability of the hydrotropic acids to protect guinea pigs against anaphylaxis. Among the substances tested were racemic flurbiprofen, (+) flurbiprofen and (-) flurbiprofen.
  • the (+) isomer had more than a two-fold effect over the racemate; at 80% protection, the (+) isomer was 5 to 7 times more active than the racemic mixture.
  • the (-) isomer was the least active of the three compounds.
  • 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. Severe reactions due to excessive exposure involve the development of vesicles or bullae as well as the constitutional symptoms of fever, chills, weakness, and shock.
  • Energy emissions from the sun include radiation wavelengths ranging from 200 nm to more than . 18,000 nm.
  • Ultraviolet radiation is in the 200-400 nm range, and this spectrum is subdivided into three bands.
  • 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.
  • This type of burning differs from sunburn in that it is due to generated heat rather than a photochemical reaction.
  • 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.
  • 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 flurbiprofen on ultraviolet B induced erythema in human subjects. All three drugs were comparable in reducing the sunburn response to ultraviolet radiation.
  • S(+) flurbiprofen 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 flurbiprofen in its racemic form.
  • S(+) flurbiprofen 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(+) flurbiprofen substantially free of R(-) flurbiprofen.
  • 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(+) flurbiprofen substantially free of R(-) flurbiprofen.
  • 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(+) flurbiprofen substantially free of R(-) flurbiprofen.
  • S(+) flurbiprofen is associated with a nontoxic topical pharmaceutically acceptable inert carrier or diluent therefor.
  • flurbiprofen or “racemic flurbiprofen” as used herein is intended to encompass not only ( ⁇ )-2-fluoro- ⁇ -methyl-[1,1'-biphenyl]-4- acetic acid itself but also any pharmaceutically acceptable salt thereof.
  • S(+) flurbiprofen as used herein is intended to encompass not only the preferred free acid dextrorotatory or S(+) isomer of 2-fluoro- ⁇ - methyl-[1,1'-biphenyl]-4-acetic acid but also includes the pharmaceutically acceptable, antierythematously effective simple metal salts thereof, e.g., Na, K and Ca.
  • pharmaceutically acceptable, antierythematously effective simple metal salts thereof e.g., Na, K and Ca.
  • S(+) flurbiprofen means that the S(+) flurbiprofen is sufficiently free of R(-) flurbiprofen [which is the levorotatory form or R(-) isomer of 2-fluoro- ⁇ -methyl- [1,1'-biphenyl]-4-acetic acid or salt thereof] to exert the desired sustained and enhanced analgesic effect. Practically speaking, this means that the active ingredient should contain at least 90% by weight S(+) flurbiprofen and 10% or less by weight R(-) flurbiprofen.
  • the weight ratio of S(+) flurbiprofen to R(-) flurbiprofen is greater than or equal to 20:1, more preferably greater than 97:3.
  • the S(+) flurbiprofen is 98, 99 or more % by weight free of R(-) flurbiprofen, i.e., the weight ratio of S to R is approximately equal to or greater than 98:2 or 99:1.
  • Topical S(+) flurbiprofen in accord with the present invention, produces the following unexpected results:
  • the S(+) isomer of flurbiprofen is more potent than racemic flurbiprofen for topical administration on a mammal since the flurbiprofen is substantially, or in large part, in the active form;
  • S(+) flurbiprofen applied in the same amount as racemic flurbiprofen would provide a better response for preventing or treating ultraviolet radiation-induced erythema.
  • S(+) flurbiprofen would be at least twice as potent.
  • the precise amount of topical S(+) flurbiprofen 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. For use in humans, the amount effective to prevent or treat ultraviolet radiation- induced erythema of S(+) flurbiprofen will typically be from about 0.5 wt. % to about 10 wt.
  • the preferred composition contains about 1 wt. % to about 5 wt. %, more preferably about 2.5 to 3.5 wt. % flurbiprofen. The most preferred composition would likely contain about 3.0 wt. % flurbiprofen. 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(+) flurbiprofen 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(+) flurbiprofen 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(+)- flurbiprofen as a sunscreen-sunburn preventive agent, a ⁇ unscreen-suntanning agent a ⁇ d/or a sunscreen-opaque sunblock agent.
  • S(+)- flurbiprofen as a sunscreen-sunburn preventive agent
  • ⁇ unscreen-suntanning agent a ⁇ d/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, pr ⁇ py
  • the topical composition of the present invention it would be advantageous for the topical composition of the present invention to have sufficient substantivity to withstand exposure of the skin to swimming, high humidity and sweating.
  • sunscreens should be applied approximately 30 minutes before exposure to the sun.
  • aminobenzoic acid and its esters are more effective if applied two hours before exposure.
  • Pre-application of . the topical S(+) flurbiprofen composition prior to sun exposure to the skin is advantageous because it allows the S(+) flurbiprofen to penetrate and perhaps bind with the skin.
  • the amount of S(+) flurbiprofen 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. %, more preferably about 2.5 wt. % to about 3.5 wt. %, most preferably 3.0 wt. %, S(+) flurbiprofen 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(-) flurbiprofen.”
  • the topical S(+) flurbiprofen 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 (amyldimethyl)
  • 2-phenyl-benzimidazole-5-sulfonic acid 1.0-4.0 triethanolamine salicylate 5.0-12.0 red veterinary petrolatum 30.0-100 titanium dioxide 2.0-25.0
  • 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 Piz Buin-8 5% ethyl-hexyl-p- Cream methoxycinnamate +
  • 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. 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. These formulations are cosmetically unpleasing, unacceptable to many patients, and are often occlusive and messy to use. 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(+) flurbiprofen may be combined along with any of the compounds identified in any of the Tables identified above as a topical vehicle for administration.
  • the patient may desire a suntan product.
  • 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, butamben picrate, dibucaine, tetracaine hydrochloride, tripelennamine , and menthol benzocaine.
  • the antimicrobial component of commercial products currently include: benzethoniu chloride, benzalkonium chloride, povidone-iodine, chloroxylenol , chlorobutanol, 8-hydroxyquinoline, phenol, 8-hydroxyquinoline sulfate, cresol-camphor complex, chlorothymol, methylbenzethonium chloride, triclosan, benzyl alcohol, and parahydracin.
  • S(+) flurbiprofen 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 flurbiprofen.
  • HPLC methods other than Maitre et al's for resolving enantiomers of NSAID's such as flurbiprofen, ketoprofen and fenoprofen, and likely adaptable to resolution of flurbiprofen include the method of Doyle et al, Pharm. Technol..9f2) , 28-32 (1985), which utilizes conversion of the racemate to its amide derivatives for effective resolution; that of Wainer et al, J. Chromatogr. 284(1,. 117-124 (1984), which utilizes conversion of the drug to 1- naphthalene ethylamide derivatives; and that of Sallustio et al, J_-_ Chromatogr.. 374. 329-337 (1986) , which employs conversion of the drug to the R and S derivatives of R-2-phenylethylamine.
  • 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 or-methylbenzyla ine and involves preparation of the diastereoisomeric NSAID- ⁇ -methylbenzylamide directly by means of a coupling agent (e.g., 1,1'-carbonyl- diimidazole) or via the NSAID acid chloride (prepared with thionyl chloride) .
  • a coupling agent e.g., 1,1'-carbonyl- diimidazole
  • NSAID acid chloride prepared with thionyl chloride
  • the S(+) isomer can be separated from racemic flurbiprofen by preparing a salt of flurbiprofen 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(+) flurbiprofen.
  • 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(2) r 269-273 (1976) , which relates to resolution of flurbiprofen.
  • S(+) flurbiprofen may be conveniently obtained by resolution of racemic flurbiprofen, it may also be possible to utilize a chemical or microbiological synthetic process which will provide the S(+) enantiomer directly.
  • One such chemical process is provided by Schloemer United States Patent No. 4,542,237, which describes a process for preparing ⁇ -arylalkanoic acids utilizing novel ⁇ -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 flurbiprofen but which may be flurbiprofen 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(+) flurbiprofen 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(+) flurbiprofen When S(+) flurbiprofen is to be employed in the form of a pharmaceutically acceptable.
  • analgesically active simple metal salt thereof such salt may be conveniently prepared by direct salification of S(+) flurbiprofen by known methods. See, for example, deVincentiis United States Patent No. 4,440,787, which describes salts of (2',4'- difluoro-4-biphenyl)oxypropionic acid with metallic ions, such as sodium, potassium, magnesium and calcium. Nonetheless, the free acid form is the preferred. Compare also Armitage et al United States Patent No. 4,501,727, issued February 26, 1985, which describes the N-methyl-D-glucamine salt of flurbi ⁇ profen.
  • Such a salt may not only be used in oral or rectal compositions, but, because it is highly soluble in water, it may be used in the preparation of aqueous solutions of S(+) flurbiprofen salt for parenteral injection, as indicated by Armitage et al.

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Abstract

Des érythèmes provoqués par le rayonnement ultraviolet sont prévenus ou traités chez un humain requérant une telle prévention ou un tel traitement, c'est-à-dire un mammifère souffrant de coups de soleil ou cherchant à les éviter, par l'administration topique d'une quantité efficace d'une dose unitaire prévenant ou traitant les érythèmes, de l'énantiomère de flurbiprofène S(+), ledit énantiomère étant pratiquement dépourvu de son antipode de flurbiprofène R(-).
PCT/US1991/006881 1990-10-05 1991-09-26 Prevention ou traitement de coups de soleil au moyen de l'isomere s(+) de flurbiprofene WO1992005768A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995023596A1 (fr) * 1994-03-05 1995-09-08 The Boots Company Plc Formulations pharmaceutiques topiques depourvues d'adhesif
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
EP1476127A4 (fr) * 2002-01-25 2010-01-06 Pharmaqest Pty Ltd Formulations topiques contenant des anti-inflammatoires non steroidiens (ains) qui presentent une activite chimiopreventive
EP2468270A1 (fr) 2010-12-21 2012-06-27 GALENpharma GmbH Acide (R)-2-(3-fluoro-4-phénylphényl)propionique pour une utilisation dans le traitement de maladies cutanées

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Cited By (12)

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WO1995023596A1 (fr) * 1994-03-05 1995-09-08 The Boots Company Plc Formulations pharmaceutiques topiques depourvues d'adhesif
AU691583B2 (en) * 1994-03-05 1998-05-21 Boots Company Plc, The Adhesive free topical pharmaceutical formulations
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
EP1476127A4 (fr) * 2002-01-25 2010-01-06 Pharmaqest Pty Ltd Formulations topiques contenant des anti-inflammatoires non steroidiens (ains) qui presentent une activite chimiopreventive
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
EP2468270A1 (fr) 2010-12-21 2012-06-27 GALENpharma GmbH Acide (R)-2-(3-fluoro-4-phénylphényl)propionique pour une utilisation dans le traitement de maladies cutanées
WO2012084978A1 (fr) 2010-12-21 2012-06-28 Galenpharma Gmbh Acide (r)-2-(3-fluoro-4-phénylphenyl)propionique destiné à être utilisé dans le traitement de maladies de la peau

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