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WO1993010791A1 - Utilisation d'un compose chimique connu dans la production d'une composition pharmaceutique a application topique - Google Patents

Utilisation d'un compose chimique connu dans la production d'une composition pharmaceutique a application topique Download PDF

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Publication number
WO1993010791A1
WO1993010791A1 PCT/DK1992/000368 DK9200368W WO9310791A1 WO 1993010791 A1 WO1993010791 A1 WO 1993010791A1 DK 9200368 W DK9200368 W DK 9200368W WO 9310791 A1 WO9310791 A1 WO 9310791A1
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WIPO (PCT)
Prior art keywords
diflunisal
compositions
cells
produced
treatment
Prior art date
Application number
PCT/DK1992/000368
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English (en)
Inventor
Søren MOURITSEN
Henrik Elsner
Svenn Klüver JEPSEN
Original Assignee
Mouritsen & Elsner Aps
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 Mouritsen & Elsner Aps filed Critical Mouritsen & Elsner Aps
Priority to JP5509737A priority Critical patent/JPH07505128A/ja
Priority to EP93900020A priority patent/EP0614365A1/fr
Publication of WO1993010791A1 publication Critical patent/WO1993010791A1/fr

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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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention concerns the use of the compound di- flunisal (5-( 2,4-difluorophenyl)-salicylic acid) of the formula:
  • psoriasis is a cro- nic skin disease of unknown etiology.
  • the indidence is about 2-3% in most western countries.
  • the disease is here ⁇ ditary, presumably polymerically conditioned, with irregu ⁇ larly occurring manifestations that may be caused mechani ⁇ cally, but probably also by other influences, infections, psychic strain, etc.
  • the onset of the disease is usually at the age of 20-30. It manifests itself as regular, slightly infiltrated, hyperemic pat - which are covered by stearin-like scales consisting o.. ⁇ »any layers.
  • the dis ⁇ ease is localized to the epidermis, and it is character- ized by increased cell turnover.
  • the normal cell turnover which means the time it takes for a recently formed cell to get from the basal cell layer to the horny layer at the surface of the skin, is usually about 4 weeks, but in case of psoriasis it just takes 2-3 days. According to the clinical nature of the disease a distinc ⁇ tion is made between a number of different clinical forms, all of which are comprised by the designation "psoriasis" in the present context.
  • a plurality of modes of treatment have been employed in the course of time with a view to keeping the disease under control (1):
  • drugs are used for topical appli ⁇ cation, such as corticosteroids, calcipotriol, anthralin (dithranol) and coal tar.
  • systemic treat ⁇ ment with drugs is used, such as methotrexate or aromatic retinoids, and phototherapy alone or in combination with psoralens. Combinations of these systemic and topical modes of treatment have been in general use in recent years.
  • Topically applied corticosteroids are moreover rendered more or less ineffective after a re- latively short time.
  • Anthralin is difficult to administer for the patient owing to discoloration and a considerable risk of inducing serious irritations, although these draw ⁇ backs have been mitigated to some extent after the intro ⁇ duction of the so-called minute therapy, comprising apply- ing the drug to the skin for just 10-30 minutes.
  • Topical treatment with tar is not used very much in Europe, in contrast to the widespread use in the USA where the treat ⁇ ment is considered rather effective when the tar applica ⁇ tion is followed by UVB iradiation (Goeckermann's treat- ment). However, the treatment with tar is inexpedient, because the tar composition is greasy and malodorous.
  • methotrexate Systemic use of methotrexate is probably one of the most effective methods for the treatment of psoriasis in pa- tients who are not in the fertile age, but it involves a potential risk of liver side effects, and it is therefore to be supervised carefully.
  • Retinoids may be used, but serious side effects in this connection have been reported. These comprise induction of liver side effects and in some cases articular deforma ⁇ tions.
  • Etretinate igason®
  • Etretinate which is so far the only aromatic retinoid introduced for the treatment of psoria ⁇ sis, is moreover teratogenic, and since its half life in the body is long, it is recommended that pregnancy during the treatment or within the first 12 months after the ces ⁇ sation of the treatment should be interrupted by abortion.
  • the D vitamin analog compound calcipotriol is another applicable agent for the treatment of psoriasis, because the compound inhibits the proliferation of the epidermal cells (2).
  • it is marketed as an ointment, which may be inconvenient to use for the patient, and the medi ⁇ cament is not recommended for use on pregnant women owing to the still limited experience.
  • the T cell inhibiting substance cyclosporin A has a clear effect on inflammatory diseases, such as e.g. psoriasis (3).
  • the substance has a number of adverse sys ⁇ temic side effects and is moreover difficult to use lo- cally.
  • T lymphocytes play a part (4,5,6,7).
  • diseases are moreover characterized by a generally increased cell proliferation of e.g. inflamma ⁇ tory cells, including T cells, and possibly of epidermal cells.
  • a topical drug against psoriasis and other inflammatory and/or autoimmune diseases must satisfy the following requirements:
  • SASP sulfasalazine
  • diflunisal has the necessary effect with respect to inhibition of cell proliferation of disease-relevant cells, and since the compound has moreover been found to be absorbed surprisingly easily through the skin without giving rise to inconvenient side effects, it is extremely suitable for the production of topical drugs against pso ⁇ riasis and other inflammatory diseases.
  • diflunisal can be formulated as eye agents for the treatment of uveitis and as agents intended for local treatment in the intestinal canal, as well as optionally as agents that can be used on other body surfaces.
  • Diflunisal is a well-known medicament of analgesic and antiinflammatory activity (8).
  • the substance is known from the analgesic compositions Diflonid® and Dono- bid®, both of which are in tablet form.
  • the substance has not yet been marketed in the form of compositions for to ⁇ pical administration, although other modes of administra- tion for diflunisal than the oral- one have been studied.
  • compositions for e.g. vaginal and rectal administra ⁇ tion of diflunisal can be prepared with a view to treat ⁇ ment of inflammatory diseases, but it is necessary here to use hydrogenated phospholipids and a fatty base material to increase the bioavailablity of diflunisal which has poor absorbability through mucosal membranes.
  • compositions for the treatment of i.a. psoriasis preferably for topical application.
  • These compositions comprise the substances 4- aminosalicylic acid (4-ASA), 5-aminosalicylic acid (5-ASA) or functional derivatives thereof.
  • Diflunisal is not com- prised by the patent claims of this reference.
  • the clini ⁇ cal results with respect to the action of 5-ASA on psoria ⁇ sis are still uncertain, and 5-ASA moreover gives rise to discoloration of the skin after oxidation with the oxygen of the air.
  • the compound has a well-documented useful activity against Crohn's disease and colitis ulce- rosa, the mode of action has still not been fully ex ⁇ plained.
  • diflunisal can be used per- orally against psoriasis.
  • the mode of action is stated to be based on inhibition of lipoxygenase, interfering with the biotransformation of arachidonic acid to LTB. (leuko- triene B. and 5-HETE (5-hydroxyeicosa[5.8.10.14]tetraeno- ate). This is said to counter the psoriasis attack which gives high arachidonic acid and 5-HETE levels.
  • diflunisal can be for ⁇ mulated for a plurality of different modes of administra ⁇ tion in connection with the present use of diflunisal for the production of topical drugs against inflammatory and/or autoimmune diseases.
  • drug forms for topical application may occur in various states (solutions, emulsions, suspen ⁇ sions) based on various vehicles.
  • states solutions, emulsions, suspen ⁇ sions
  • drug forms for topical application may occur in various states, as illustrated in the table.
  • Taxonomy according to state and drug forms.
  • NSAID Non Steroid Anti Inflammatory Drug
  • mice of either the Balb/c type or the Blab/k type were used in all the experiments.
  • the mice were immunized with a single injection in hind paws and tail stub with 0.1 ml of a water-in-oil emulsion containing equal parts of phosphate buffered salt water (PBS) and complete Freund's adjuvant containing Mycobacterium butyricum (Dif- co) and in some experiments 1 mg/ml antigen in the form of a peptide (MP7 having the sequence PELFEALQKLFKHAY) (16).
  • PBS phosphate buffered salt water
  • Dif- co complete Freund's adjuvant containing Mycobacterium butyricum
  • MP7 having the sequence PELFEALQKLFKHAY
  • WeHi and X63 cells were cultured in RPMI with the same additions as above in microtiter plates with 4 5 x 10 cells per well. However, mouse serum was replaced by 10% foetal calf serum in the medium. The cells were cultured for 4 hours together with NSAID dilutions and 1
  • SASP Sulfasalazine
  • 5-aminosalicylic acid 5-ASA
  • SASP Sulfasalazine
  • 5-ASA 5-aminosalicylic acid
  • SASP has a direct inhibitory activity on both antigen-specific as well as Concanavalin A (Con A) stimulated murine T cell proliferation.
  • Con A Concanavalin A
  • SP sulfapyridine
  • OS olsalazine
  • Figs. 2a and 2b show partly the effect on Con A stimulated T lymphocytes and partly the effect on LPS stimulated B lymphocytes from mouse spleens. There is no difference in the inhibition of the two cell types, in contrast to the effect of the T cell specific substance cy ⁇ losporin A (CSP).
  • CSP T cell specific substance
  • salicylic acids derivatised " with e.g. an acetyl group on the OH group (acetylsalicylic acid), or in which the carboxylic acid group has been converted to an amide (salicylamide and salicyl glycine), have no noticeable effect on the cell proliferation, like 5-ASA.
  • Figs. 6a and 6b show a comparison of the effect of diclofenac, indomethacin, PS and diflunisal on the proliferation of WeHi and X63 cells, respectively. As will be seen, these compounds are sub- stantially equipotent with respect to the inhibiting effect on the cell proliferation.
  • PS is somewhat less potent, and diclofenac and indomethacin, which are not salicylic acid derivatives, but acetic acid deriva ⁇ tives, and which are therefore not chemically analogous to diflunisal, appear to exhibit less effective absorption through the skin. This makes these substances less inter ⁇ esting in the present context.
  • indomethacin and diclofenac are known to be locally irritating, and diclofenac moreover exhibits photosensibility, which makes the substances unuseful for local application.
  • Diflunisal is absorbed almost completely after oral ad ⁇ ministration of doses of 50-500 mg.
  • the oral bioavail- ability is stated in the literature to be 100% based on recovery in the urine after 96 hours.
  • Diflunisal is greatly bound to plasma proteins (20). The elimination is concentration dependent and depends upon conjugation with glucuronic acid. About 80-95% of an oral dose is secreted in the urine 72-96 hours after ad ⁇ ministration, mainly as phenol (64%) and acyl glucuronides (20%).
  • diflunisal for the treatment of psoriasis will be conditional upon the substance penetrating into the skin.
  • diflunisal in propylene glycol was followed by collection of urine round the clock, which was analyzed on HPLC for diflunisal content. As appears from table 2, diflunisal can be absorbed very well through the skin and then be secreted in the urine.
  • Diflunisal has thus been present in the epidermis, where the substance may give rise to inhibition of the prolife ⁇ ration of the epidermal cells as well as the pathogenic T cells.
  • cremes including foam
  • foam it is possible i.a. to vary the lipophilicity and the viscosity of the base, whereby the drug release from the creme can be con ⁇ trolled.
  • foam quality by varying the content of isobutane.
  • the formulation can also be varied with respect to penetration enhancing sub ⁇ stances, so-called enhancers, e.g. ethanol and Azone®.
  • enhancers e.g. ethanol and Azone®.
  • When formulating gels it is possible to formulate a hydro ⁇ phobic as well as a hydrophilic gel. It applies to both of them that they will dry on the skin after application, thereby forming a firm brittle film.
  • Hydrophilic gels have the advantage that they are not greasy. They can moreover be removed by ordinary washing, which is of importance in case of e.g. application on heary skin portions.
  • Hydrophobic ointments are ointments based on lipophilic vehicles, typically hydrocarbons, vegetable oils, semi- synthetic fats, waxes and alkyl polysiloxanes. Hydrophobic ointments absorb moisture from the skin only to a limited extent, and they therefore have an occlusive effect. They also have a good skin contact and have a softening effect on the horny layer after application for an extended pe ⁇ riod of time, which is desirable when the horny layer is thick.
  • Hydrophobic ointments also have a positive effect on scaly skin areas.
  • Hydrophilic ointments are based on carriers which are miscible with water, most frequently polyethylene glycols.
  • Water emulsi- fying ointments are based on lipophilic vehicles admixed with lanolin or other w/o emulsifying substances, e.g. sorbitan esters.
  • aqueous formulations are the most common dosage form. Since diflunisal is sparingly soluble in water at a neutral pH, eye drops containing diflunisal will preferably be suspensions. The advantage of these is that the particles, after application, settle in the conjunctival sack of the eye in which they are dis- solved slowly. This provides a depot effect.
  • micronized diflunisal is preferably to be used, which means that the greater part of the particles is smaller than 5 ⁇ m and all the particles are smaller than 25 ⁇ M.
  • Diflunisal can also be formulated in a controlled release form for the treatment of inflammatory intestinal di ⁇ seases, cf. reference (21). Formulation of enemas is also possible.
  • Non-aqueous foam Diflunisal 0.01 - 10 %
  • Aqueous foam is aqueous foam
  • the produced foam bases are packed in aluminium cans which are closed with a valve, following which a dosing device is applied, which makes it possible to dispense doses from 1 to 5 ml.
  • a valve with a dosing device is available e.g. from Lablabo, 5 rue Roger Salengro, 92120 Montrouge, France.
  • Methylcellulose 0 - 5 %
  • Natural starches 0 - 25 %
  • Macrogol 400 60 % Macrogol 3350 30 - 40 %
  • Preservative e.g. benzalconium chloride
  • Paraffin oil up to 100 %
  • Fig. 1 Study of the ability of various SASP analog sub ⁇ stances to inhibit the T cell activation, a. In- hibition of the antigen-specific T cell response to the synthetic peptide MP7 (PELFEALQKLFKHAY) with various concentrations of SASP, SP and 5- ASA. b. Inhibition of Con A stimulated T cells from spleens with various concentrations of SASP, SP, 5-ASA and Olsalazine.
  • SASP specifically inhibit T-cells.
  • the unit on the top x-axes is the concentration range of CSP.
  • Fig. 3 Study of the effect of various SASP analog sub ⁇ stances on two immunologically relevant tumor lines, a. Inhibition of the growth of WeHi cells (monocyte/macrophage line) of SASP, SP, 5-ASA and Olsalazine. b. Inhibition of the growth of X-63 cells (myeloma line) with the same substances.
  • Fig. 4 Study of the proliferation inhibition of T and B cells by addition of salicylic acid analog sub- stances derivatised on the carboxylic acid group and the phenol group, respectively, a. Inhibition of Con A stimulated T cells from spleens with various concentrations of acetylsalicylic acid, salicylamide, salicyl glycine and 5-ASA. b. Inhi ⁇ bition of LPS stimulated B cells with the same substances.
  • Fig. 5 Study of the proliferation inhibition of T and B cells by addition of salicylic acids derivatised in the 5-position.
  • Inhibition of WeHi cells with the same substances
  • d Inhibition of X-63 cells with-the same substances. ----
  • Fig. 6 Study of the proliferation inhibition of tumor cells by addition of inhibitors of the oxidative phosphorylation. a. Inhibition of WeHi cells with diclofenac, indomethacin, diflunisal and phenyl- salicylic acid. b. Inhibition of X-63 cells with the same substances.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Composé appelé diflunisal (acide 5-(2,4-difluorophényle)-salicylique) et répondant à la formule (I). Il est utilisé dans la production d'une composition pharmaceutique destinée au traitement des maladies inflammatoires et/ou auto-immunes telles que le psoriasis, la maladie de Crohn et l'uvéite. De préférence, on produit des compositions, par exemple des crèmes ou des pommades, destinées à être utilisées de manière locale à la surface de la peau, des agents ophtalmologiques, des compositions destinées au traitement local de la portion intestinale du tube digestif, des agents administrés par voie vaginale, des compositions destinées à être utilisées de manière locale dans la cavité buccale, ainsi que des compositions pour inhalation.
PCT/DK1992/000368 1991-12-05 1992-12-04 Utilisation d'un compose chimique connu dans la production d'une composition pharmaceutique a application topique WO1993010791A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5509737A JPH07505128A (ja) 1991-12-05 1992-12-04 局所投与用薬学的組成物の調整の為の公知化合物の使用
EP93900020A EP0614365A1 (fr) 1991-12-05 1992-12-04 Utilisation d'un compose chimique connu dans la production d'une composition pharmaceutique a application topique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1965/91 1991-12-05
DK911965A DK196591D0 (da) 1991-12-05 1991-12-05 Anvendelse af en kendt kemisk forbindelse til fremstilling af et farmaceutisk paraeparat til topisk applikation

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WO1993010791A1 true WO1993010791A1 (fr) 1993-06-10

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PCT/DK1992/000368 WO1993010791A1 (fr) 1991-12-05 1992-12-04 Utilisation d'un compose chimique connu dans la production d'une composition pharmaceutique a application topique

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EP (1) EP0614365A1 (fr)
JP (1) JPH07505128A (fr)
AU (1) AU3157093A (fr)
CA (1) CA2124852A1 (fr)
DK (1) DK196591D0 (fr)
WO (1) WO1993010791A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049276A3 (fr) * 1999-12-29 2001-12-13 Cosmo Spa Compositions pharmaceutiques pour l'administration topique dans la cavite buccale de produits anti-inflammatoires non steroides utiles pour les therapies anti-inflammatoires et analgesiques stomatologiques, de la bouche et de la cavite buccale
US9186358B2 (en) 2009-11-18 2015-11-17 Galderma Laboratories, L.P. Combination therapy for treating or preventing an inflammatory skin disorder
WO2018130679A1 (fr) * 2017-01-16 2018-07-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour réduire la motilité cellulaire médiée par cd95

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09278653A (ja) * 1996-04-05 1997-10-28 Santen Pharmaceut Co Ltd 網膜疾患治療剤
US7985415B2 (en) 1997-09-10 2011-07-26 Rutgers, The State University Of New Jersey Medical devices employing novel polymers
CN1674868B (zh) * 2002-07-23 2010-09-29 诺瓦提斯公司 包含药物、软膏基质和增溶剂/分散剂的眼用软膏剂组合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4483854A (en) * 1983-04-12 1984-11-20 Key Pharmaceuticals, Inc. Systemic treatment of psoriasis using certain salicylates
DE3605345A1 (de) * 1986-02-20 1987-08-27 Theodor Prof Dr Eckert Verwendung organischer salze des diflunisal in einer cutanen applikationsform
US4748174A (en) * 1986-01-03 1988-05-31 Therapicon S.R.L. Water soluble salts of an NSAID with meglumine/glucamine
EP0270316A2 (fr) * 1986-12-04 1988-06-08 Pfizer Inc. Compositions topiques contenant des imidazoles 1-substitués et des agents non-steroides anti-inflammatoires pour le traitement de l'acné
EP0275526A2 (fr) * 1986-12-27 1988-07-27 Banyu Pharmaceutical Co., Ltd. Composition pour l'administration par une cavité corporelle

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4483854A (en) * 1983-04-12 1984-11-20 Key Pharmaceuticals, Inc. Systemic treatment of psoriasis using certain salicylates
US4748174A (en) * 1986-01-03 1988-05-31 Therapicon S.R.L. Water soluble salts of an NSAID with meglumine/glucamine
DE3605345A1 (de) * 1986-02-20 1987-08-27 Theodor Prof Dr Eckert Verwendung organischer salze des diflunisal in einer cutanen applikationsform
EP0270316A2 (fr) * 1986-12-04 1988-06-08 Pfizer Inc. Compositions topiques contenant des imidazoles 1-substitués et des agents non-steroides anti-inflammatoires pour le traitement de l'acné
EP0275526A2 (fr) * 1986-12-27 1988-07-27 Banyu Pharmaceutical Co., Ltd. Composition pour l'administration par une cavité corporelle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
International Journal of Pharmaceutics, Volume 19, 1984, FRITS MOOLENAAR et al., "Rectal versus oral absorption of diflunisal in man", page 161 - page 167, see especially page 162, lines 4-13. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049276A3 (fr) * 1999-12-29 2001-12-13 Cosmo Spa Compositions pharmaceutiques pour l'administration topique dans la cavite buccale de produits anti-inflammatoires non steroides utiles pour les therapies anti-inflammatoires et analgesiques stomatologiques, de la bouche et de la cavite buccale
US9186358B2 (en) 2009-11-18 2015-11-17 Galderma Laboratories, L.P. Combination therapy for treating or preventing an inflammatory skin disorder
WO2018130679A1 (fr) * 2017-01-16 2018-07-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour réduire la motilité cellulaire médiée par cd95

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CA2124852A1 (fr) 1993-06-10
AU3157093A (en) 1993-06-28
DK196591D0 (da) 1991-12-05
EP0614365A1 (fr) 1994-09-14
JPH07505128A (ja) 1995-06-08

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