WO2001019358A2 - Compositions pharmaceutiques destinees au traitement du psoriasis - Google Patents

Compositions pharmaceutiques destinees au traitement du psoriasis Download PDF

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Publication number
WO2001019358A2
WO2001019358A2 PCT/EP2000/008879 EP0008879W WO0119358A2 WO 2001019358 A2 WO2001019358 A2 WO 2001019358A2 EP 0008879 W EP0008879 W EP 0008879W WO 0119358 A2 WO0119358 A2 WO 0119358A2
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WO
WIPO (PCT)
Prior art keywords
dexrazoxane
medicament
calculated
injection
infusion
Prior art date
Application number
PCT/EP2000/008879
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English (en)
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WO2001019358A3 (fr
Inventor
Iervant Zarmanian
Jadranka Rogan-Grgas
Original Assignee
Cyathus Exquirere Pharmaforschungs Gmbh
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
Priority to EP00960646A priority Critical patent/EP1214073A2/fr
Priority to CA002384685A priority patent/CA2384685A1/fr
Priority to US10/070,687 priority patent/US6693100B1/en
Priority to SK280-2002A priority patent/SK2802002A3/sk
Application filed by Cyathus Exquirere Pharmaforschungs Gmbh filed Critical Cyathus Exquirere Pharmaforschungs Gmbh
Priority to BR0013921-1A priority patent/BR0013921A/pt
Priority to MXPA02002486A priority patent/MXPA02002486A/es
Priority to AU72865/00A priority patent/AU7286500A/en
Priority to KR1020027003049A priority patent/KR20020035131A/ko
Priority to EEP200200128A priority patent/EE04871B1/xx
Priority to HU0202791A priority patent/HUP0202791A3/hu
Priority to PL00354980A priority patent/PL354980A1/xx
Publication of WO2001019358A2 publication Critical patent/WO2001019358A2/fr
Publication of WO2001019358A3 publication Critical patent/WO2001019358A3/fr
Priority to BG106428A priority patent/BG106428A/xx
Priority to HR20020201A priority patent/HRPK20020201B1/xx

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P17/06—Antipsoriatics

Definitions

  • This invention relates to pharmaceutical compositions based on l,2-bis(3,5- dioxopiperazin-l-yl)-propane and pharmaceutically acceptable salts thereof.
  • razoxane The racemic dl-form of l,2-bis(3,5-dioxopiperazin-l-yl)-propane is known as razoxane.
  • Compounds of this kind belong to the family of bis-dioxopiperazines, which have been known for a long time, particularly as anti-tumor agents. This class of compounds, their use and preparation are described in, e.g. GB-A-1 234 935, GB- A-l 374 979, US-A-4 275 063, EP-A1 491 053, EP-A1 256 137, EP-A1 230 474, EP-A2 014 327 and EP-A1 125 475.
  • the bis-dioxopiperazines represent lipophilic derivatives of EDTA (ethylene diamino tetraacetic acid), a substance known as a chelating agent. As such they are thought to act by chelating iron, thereby reducing site-specific oxygen radical production.
  • the bis-dioxopiperazines exert topoisomerase II inhibitory activity which presumably is responsible for the anti tumor activity of these drugs.
  • the d-enantiomer of razoxane is known as dexrazoxane.
  • the current clinical use of dexrazoxane is to prevent doxorabicin-induced cardiac disease in patients with metastatic breast cancer.
  • Dexrazoxane is commercially available as the hydrochloride salt.
  • dexrazoxane. HC1 is available from Chiron, Inc under the registered trade mark Cardioxane, whilst in the US it is available from Pharmacia Upjohn under the registered trade mark Zinecard.
  • GB-A-1 234 935 is one of the oldest publications on bis-dioxopiperazines and describes their preparation through cyclisation of the corresponding tetracarboxamidomethyl derivatives through heating together with polyphosphoric acid.
  • the therapeutic spectrum of these drugs includes certain forms of cancer, including leukaemia, and certain non-malignant forms of proliferative disease.
  • Psoriasis is a chronic skin disease characterised by scaling and inflammation.
  • the cause of psoriasis is unknown but recent research indicates that it is likely to be an autoimmune disease.
  • Psoriasis is a serious and unpleasant condition which has no cure and not all treatments work for each individual.
  • Psoriasis can be very painful, but the pain is more than skin deep.
  • the emotions suffer as well. It presents people with physical limitations, disfiguration, and its tedious daily care always demands too much time. Embarrassment, frustration, fear and depression are common. In extreme cases, a loss of self-esteem results in a complete withdrawal from society.
  • Various kinds of temporary relief are available and they work with varying degrees of success. Treatments and medications are often time consuming and expensive but one thing is certain: the symptoms may come and go, but they almost always come again. It is a lifelong disease.
  • Step 1 is topical treatment
  • step 2 is phototherapy
  • step 3 is systemic treatment.
  • Medicines currently prescribed for systemic treatment are the immunosuppressants methotrexate and cyclosporine A, hydroxyurea and retinoids.
  • Methotrexate and cyclosporine A have unpleasant and potentially dangerous side effects. Moreover, all these treatments leave patients with recurrent psoriasis and because different patients respond differently to varying treatments, it would be very welcome to have additional weapons in the therapeutic armoury.
  • razoxane was not developed further and today is not recommended for treatment of psoriasis. Hitherto, therefore, the known facts about razoxane have been that it cannot be used both safely and effectively to treat psoriasis.
  • a new pharmaceutical composition for treatment of psoriasis contains as active compound dexrazoxane, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier and/or excipient.
  • the invention also includes a method of treating psoriasis in a patient, comprising administering to the patient a therapeutically effective amount of dexrazoxane, the d- isomer of l,2-bis(3,5-dioxopiperazin-l-yl)-propane, a compound of formula
  • PASI Psoriasis Area and Severity Index
  • the method may comprise administering the dexrazoxane by injection or infusion (or by other internal administration route, for example oral) at a daily dosage of, for example, between 250mg and 1750mg, and in one suitable protocol comprises administering the dexrazoxane at increasing dosages, for example at a first daily dosage for an initial period of up to e.g. 5 days, a second daily dosage for a second period of up to e.g. 5 days and a third daily dosage for a third period of up to e.g. five days.
  • the initial, second and third periods may be spaced apart and preferably are one or two days long; one of the initial, second and third periods is dispensed with in some treatment protocols.
  • the first daily dosage is usually from about 250mg to about 750mg (e.g. about 500mg)
  • the second daily dosage is usually from about 750mg to 1250mg (e.g. about lOOOmg)
  • the third daily dosage is usually from about 1250mg to 1750mg (e.g. about 1500mg).
  • administering dexrazoxane involve administering the dexrazoxane at intervals, for example with an interval between administration periods of from 5 to 20 days, more usually from 8 to 16 days and most preferably of from 10 to 14 days, e.g. 12 days.
  • an administration period may last two successive days, on each of which dexrazoxane is administered.
  • single day administration periods may be used, or administration periods of more than two days, in which case dexrazoxane may be administered on all of the days or only some of them.
  • Particularly preferred protocols consist of three spaced administration periods, for example of two days in length and/or separated by intervals of 12 days; thus a protocol may consist of the three cycles appearing in Figure 1.
  • the administration protocol may be repeated as necessary, for example after a period of between a month and a year or more.
  • the parenteral administration is suitably by infusion or injection and the dexrazoxane is usually (but not exclusively) administered in the form of a salt.
  • the dosage may be varied, for example increased, over the course of the treatment.
  • the dosage may be increased after the first administration period of the protocol described in the previous paragraph if the patient's initial response is not adequate.
  • an adult is administered a dose of from about 250mg to about 750mg on each day of an initial two day administration period, after which the dose may be maintained or increased (e.g. to about 750mg to about 1250 mg).
  • the dosage may be maintained or, if necessary increased (or even decreased) for the third administration period.
  • the dosage is conveniently, but not necessarily, altered in steps of 500mg.
  • dexrazoxane weights and weight percentages specified in this application refer to dexrazoxane hydrochloride, i.e. they relate to dexrazoxane as the hydrochloride salt. If an alternative form is used appropriate adjustments should be made on the basis of the relative molecular weights of the two forms. Similarly, dosages must be suitably adjusted for the treatment of children.
  • the dexrazoxane is administered intravenously or otherwise by injection or infusion.
  • the solutions for injection or infusion are made by reconstituting lyophilised dexrazoxane just prior to administration.
  • the lyophihsate may be packaged in an amount corresponding to the unit dosage to be used and packages containing about 250mg, from about 750 mg to about 1250 mg or about 1250 mg to about 1750 mg are each included in the invention.
  • the invention also includes the use of dexrazoxane to manufacture liquid dexrazoxane preparations in ready to use form, and the administration of such ready to use liquid formulations (solutions).
  • the dexrazoxane is administered topically, transdermally or percutaneously, e.g. in the form of an ointment, lotion or plaster.
  • Other methods comprise the oral administration of the dexrazoxane, for example in tablet form.
  • the dexrazoxane may be administered in the form of a suppository.
  • the dexrazoxane is administered as a topical formulation, for example as an ointment, cream or gel.
  • the concentration of dexrazoxane is not critical.
  • topical formulations contain at least 0.1 wt % dexrazoxane, and more usually contain from 0.25 wt % and especially 0.5 wt % to 5 wt % or more dexrazoxane.
  • One class of formulations contains 1-2 wt % of dexrazoxane.
  • the invention includes formulations adapted for topical administration to the exclusion of oral or parenteral administration or administration by injection or infusion.
  • the topical formulations are suitably packaged in tubes of up to 1 OOg, associated with instructions to use them to treat psoriasis.
  • the topical formulations may by way of example contain conventional carriers.
  • the ointments may contain water and one or more hydrophobic carriers selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol and white vaseline.
  • the carrier compositions of the creams are typically based on water and white vaseline, in combination with glycerol and more minor components, e.g. one or more of glycerinemonostearate, PEG- glycerinemonostearate and cetylstearyl alcohol.
  • the gels may by way of example be formulated using isopropyl alcohol and water, suitably in combination with minor components, for example one or more of glycerol and hydroxyethyl cellulose.
  • the dexrazoxane may be used in combination therapy, for example with a non- steroidal anti-inflammatory drug, a TNF inhibitor or a vitamin.
  • the invention therefore includes products, especially comprising a topical formulation, containing dexrazoxane and an agent useful for treating psoriasis or relieving its symptoms as a combined preparation for simultaneous, separate or sequential use in treating psoriasis.
  • the product may be a topical formulation containing the two or more active agents in combination.
  • the patients showed marked subjective and objective responses as a 25-30% regression of the skin lesions, without experiencing the known side effects of razoxane.
  • the preferred formulation is a sterile solution for injection or infusion, but ointments, lotions, oral forms, plasters and suppositories may also be employed.
  • This patient a 55 year old male, had a 20 year history of psoriasis.
  • the disease started after mental stress (loss of near person) with a rash on the hairy part of the head. From the very onset of the disease the patient received intensive treatment with vitamins B ⁇ , B 6 , B , and calcium. He had artificial hyperthermia with pyrogenal injections, methotrexate, various ointments (e.g. salicylic ointment) under a dermatologist's observation at a specialised clinic. In spite of the treatment the psoriatic rash was spreading over the trunk, upper and lower extremities and it was accompanied by a marked general itch. The patient had practically no remissions.
  • Concurrent diseases were grade II hypertension and chronic cholecystopancreatitis.
  • the patient complained about itching all over the body (resulting in insomnia) and pain in the large joints (mainly knees).
  • the skin on the back, buttocks, chest and arms was covered with a erythematous papular and pustular rash with a white coating (desquamation).
  • a similar though less intense rash was seen on the legs.
  • the patient's general status, the haematological and biochemical profiles were within normal.
  • the patient received the first doses of Cardioxane® (dexrazoxane. HC1) at 500mg each day by intravenous drip infusion.
  • the patient reported of the amelioration of itch several hours after the first Cardioxane® administration.
  • the itch practically disappeared after the next dose of Cardioxane® therapy at lOOOmg on day 16.
  • the patient presented with amelioration of scaling, disappearance of madescence, amelioration of hypernia and flattening of rash, and complete disappearance of arthralgia.
  • the patient slept well for the first time in a long disease period. The effect was still preserved at the examination on day 29 and day 30 when the patient was given the last two injections of Cardioxane® at 1500mg each.
  • the rash first appeared on the head and the right upper limb to spread over the trunk and upper limbs later.
  • the patient had received therapies similar to the patient described in Example 1.
  • he received UV therapy, peloids, sulfurated hydrogen baths, but without lasting effect.
  • the patient had no concurrent illness except asthenia, sinus arrhythmia and left ventricular hypertrophy.
  • the skin on the back, lumbar region and shoulders was covered with merged erythematous papular, bullar and desquamating lesions.
  • the rash on the lateral chest walls and on the lower limbs was mainly erythematous and less marked.
  • the skin lesions covered about 50% of the body surface. The patient did not complain of itch.
  • the patient was given 6 intravenous drip injections with Cardioxane® according to the following schedule:
  • This patient a 37 year old female, had a 16 year history of the disease, manifesting itself after an abortion and mental stress.
  • the psoriatic rash appeared on the hairy part of the head and neck to spread further over the body.
  • the patient received insolation with but a temporary effect.
  • the patient had had 4 hospitalisations to receive therapy with vitamins, calcium, and various ointments. After a period of intense stress due to the loss of a close person the patient had a sharp exacerbation of the disease, with erythematous lesions covering most of the body.
  • the patient also had a history of periodic episodes of allergic asthmatic bronchitis.
  • eligible patients received 500mg of Cardioxane ® by intravenous infusion on each of two consecutive days. They were reviewed 7 and 14 days after the first day of treatment.
  • a third cycle of treatment was given after the same interval (days 29 and 30, in this case). Patients who showed a complete response received the same dose as they received in the second cycle, whilst one patient, who showed no response, received two doses of 1500mg.
  • the primary efficacy parameter was the percentage reduction in skin area and severity affected by psoriasis, as determined by the standardised assessment of the Psoriasis Area and Severity Index (PASI).
  • PASI Psoriasis Area and Severity Index
  • the PASI-scores ranged between 23.1 and 44.1, with a mean score of 31.9. Most of the patients did respond to the treatment, except for one patient, who was absolutely resistant to therapy.
  • the PASI-scores ranged between 3.4 and 29.7, with a mean score of 11.4.
  • the mean reduction in PASI was 65%, with a maximum reduction of 88%, and one resistant case.
  • the tolerability of the treatment was excellent, and no serious adverse events were reported.
  • the therapy with Cardioxane resulted in better and faster relief of symptoms associated with psoriatic arthritis, when compared to treatment with cyclosporine A (which is the standard treatment in this indication and had been used previously in the clinic).
  • a solution for infusion is prepared:
  • Cardioxane ® is available in 36ml brown glass vials. Each vial contains 500mg lyophilised active substance, the hydrochloric acid salt of dexrazoxane. For reconstitution the contents of each vial is dissolved in 25ml sterile water for injection. The contents will dissolve within a few minutes under gentle agitation. The pH of the resulting solution is approx. pH 1.6.
  • the solution needs to be further diluted.
  • hydroxypropylmethyl cellulose, polyvinylpyrrolidone and a sufficient amount of water are mixed together and stirred until dissolved (binder solution).
  • Cardioxane ® , starch, and the rest of the hydroxypropylmethyl cellulose are mixed in a granulator and stirred for 10 minutes.
  • the granulation process is started by spraying the binder solution. After spraying and blending the product is dried in the same apparatus and discharged when the water content is below 2.8-3.0%.
  • the granulate is passed through an oscillating granulator equipped with a 1.2mm stainless steel screen.
  • the granulate is mixed with starch, microcrystalline cellulose, and colloidal silicon dioxide for 20 minutes under rotation.
  • the magnesium stearate is added and blended with the granulate.
  • the final product is compressed at 130 mg on a rotary tableting unit equipped with 10 mm diameter lenticular punches.
  • Cardioxane is reconstituted in cold water. The other ingredients are melted at 60°C and stirred. Cardioxane ® is added and the product is stirred until cold.
  • a cream of the following composition is prepared:
  • PEG-20-glycerinmono stearate (Tagat S2 ® ) 7 g cetylstearyl-alcohol 6 g viscous paraffin 7.5 g white vaseline 25 g glycerol 85% lO g magnesium sulfate heptahydrate 0.5 g purified water 39 g
  • the glycerinemonostearate, PEG-20-glycerinemonostearate, cetylstearyl-alcohol, paraffin and vaseline are heated to 60°C and stirred.
  • the smaller part of the water is briefly boiled and cooled to 60°C, the magnesium sulfate and glycerol are added and stirred.
  • Cardioxane ® is reconstituted in the other part of the water and added to the solution. Now the two phases are emulsified in an emulsifier, and after cooling a homogeneous creme is obtained.
  • a gel of the following composition is prepared: g / lOO g gel
  • Cardioxane 1.2 g isopropyl alcohol 20 g glycerol 100 % 2 g hydroxyethyl cellulose 1.8 g purified water 75 g

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  • Oil, Petroleum & Natural Gas (AREA)
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  • Dermatology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur l'utilisation de dexrazoxane, l'isomère d de 1,2-bis(3,5-dioxopipérazin-1-yl)-propane, ou d'un sel physiologiquement acceptable de celui-ci, pour la préparation d'un médicament permettant de traiter le psoriasis.
PCT/EP2000/008879 1999-09-10 2000-09-08 Compositions pharmaceutiques destinees au traitement du psoriasis WO2001019358A2 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
MXPA02002486A MXPA02002486A (es) 1999-09-10 2000-09-08 Uso de dexrazoxano para tratar la psoriasis.
US10/070,687 US6693100B1 (en) 1999-09-10 2000-09-08 Pharmaceutical compositions for treating psoriasis
SK280-2002A SK2802002A3 (en) 1999-09-10 2000-09-08 The use of dexrazoxane, an article comprising dexrazoxane, method for treating psoriasis and method for producing a drug
KR1020027003049A KR20020035131A (ko) 1999-09-10 2000-09-08 덱스라족산의 건선 치료 용도
BR0013921-1A BR0013921A (pt) 1999-09-10 2000-09-08 Composições farmacêuticas para tratamento de psorìase
CA002384685A CA2384685A1 (fr) 1999-09-10 2000-09-08 Compositions pharmaceutiques destinees au traitement du psoriasis
AU72865/00A AU7286500A (en) 1999-09-10 2000-09-08 Pharmaceutical compositions for treating psoriasis
EP00960646A EP1214073A2 (fr) 1999-09-10 2000-09-08 Compositions pharmaceutiques destinees au traitement du psoriasis
EEP200200128A EE04871B1 (et) 1999-09-10 2000-09-08 Dekstrasoksaani kasutamine, produkt ja meetod psoriaasi raviks m?eldud ravimi valmistamiseks
HU0202791A HUP0202791A3 (en) 1999-09-10 2000-09-08 Pharmaceutical compositions for treating psoriasis
PL00354980A PL354980A1 (en) 1999-09-10 2000-09-08 Use dexrazoxane for treating psoriasis
BG106428A BG106428A (en) 1999-09-10 2002-02-22 Pharmaceutical compositions for treating psoriasis
HR20020201A HRPK20020201B1 (en) 1999-09-10 2002-03-05 Pharmaceutical compositions for treating psoriasis

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AT155899 1999-09-10
ATA1558/99 1999-09-10
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US60/183,806 2000-02-22

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CN (1) CN1378451A (fr)
AU (1) AU7286500A (fr)
BG (1) BG106428A (fr)
BR (1) BR0013921A (fr)
CA (1) CA2384685A1 (fr)
CZ (1) CZ2002729A3 (fr)
EE (1) EE04871B1 (fr)
HR (1) HRPK20020201B1 (fr)
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2021053523A1 (fr) * 2019-09-18 2021-03-25 Tryp Therapeutics Compositions et procédés pour améliorer l'effet thérapeutique de bis-dioxopipérazines

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US3941790A (en) * 1967-07-03 1976-03-02 National Research Development Corporation Bis diketopiperazines
US4275063A (en) * 1967-07-03 1981-06-23 National Research Development Corporation Pharmaceutical compositions
EP0330381A1 (fr) * 1988-02-17 1989-08-30 Erbamont, Inc. Procédé pour la préparation de (3,5-dioxopipérazinyl) -alkanes ou -alkènes
WO1995003054A1 (fr) * 1993-07-23 1995-02-02 Lxr Biotechnology Inc. Procedes de traitement de l'apoptose et d'etats associes

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US3941790A (en) * 1967-07-03 1976-03-02 National Research Development Corporation Bis diketopiperazines
US4275063A (en) * 1967-07-03 1981-06-23 National Research Development Corporation Pharmaceutical compositions
EP0330381A1 (fr) * 1988-02-17 1989-08-30 Erbamont, Inc. Procédé pour la préparation de (3,5-dioxopipérazinyl) -alkanes ou -alkènes
WO1995003054A1 (fr) * 1993-07-23 1995-02-02 Lxr Biotechnology Inc. Procedes de traitement de l'apoptose et d'etats associes

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ATHERTON D.J. ET AL: "Razoxane (ICRF 159) in psoriasis." LANCET, (1976) 2/7998 (1296). CODEN: LANCAO, XP000991316 cited in the application *
ATHERTON D.J. ET AL: "Razoxane (ICRF 159) in the treatment of psoriasis." BRITISH JOURNAL OF DERMATOLOGY, (1980) 102/3 (307-317). CODEN: BJDEAZ, XP000991409 cited in the application *
HORTON J.J. ET AL: "Long-term razoxane therapy of psoriasis." BRITISH JOURNAL OF DERMATOLOGY, (1983) 109/SUPPL. 24 (26). CODEN: BJDEAZ, XP000992104 *
MOM A. ET AL: "Razoxane in the treatment of psoriatic patients resistant to or intolerant of PUVA, methotrexate and etretinate." ACTA DERMATO-VENEREOLOGICA, (1982) 62/4 (357-358). CODEN: ADVEA4, XP000991451 *
VON HOFF D D: "Phase I trials of dexrazoxane and other potential applications for the agent." SEMINARS IN ONCOLOGY, (1998 AUG) 25 (4 SUPPL 10) 31-6. REF: 51 , XP000991547 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021053523A1 (fr) * 2019-09-18 2021-03-25 Tryp Therapeutics Compositions et procédés pour améliorer l'effet thérapeutique de bis-dioxopipérazines

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WO2001019358A3 (fr) 2001-10-04
HUP0202791A2 (hu) 2003-01-28
HRP20020201A2 (en) 2003-06-30
EP1214073A2 (fr) 2002-06-19
BR0013921A (pt) 2002-05-14
PL354980A1 (en) 2004-03-22
HUP0202791A3 (en) 2003-02-28
CA2384685A1 (fr) 2001-03-22
AU7286500A (en) 2001-04-17
KR20020035131A (ko) 2002-05-09
CN1378451A (zh) 2002-11-06
CZ2002729A3 (cs) 2002-07-17
BG106428A (en) 2003-04-30
HRPK20020201B1 (en) 2004-08-31
EE04871B1 (et) 2007-08-15
RU2002106874A (ru) 2003-11-20
EE200200128A (et) 2003-04-15
SK2802002A3 (en) 2003-02-04
MXPA02002486A (es) 2004-09-10

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